article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "To assess viral suppression rates, to assess prevalence of acquired HIV drug resistance and to characterize the spectrum of HIV-1 drug resistance mutations (HIV-DRM) in HIV-1-infected patients in a rural Tanzanian HIV cohort.\n\n\n\nThis was a cross-sectional study nested within the Kilombero and Ulanga Antiretroviral Cohort. Virological failure was defined as HIV-1 RNA ≥50 copies/mL. Risk factors associated with virological failure and with the development of HIV-DRM were assessed using logistic regression.\n\n\n\nThis study included 304 participants with a median time on ART of 3.5 years (IQR = 1.7-5.3 years); 91% were on an NNRTI-based regimen and 9% were on a boosted PI-based regimen. Viral suppression was observed in 277/304 patients (91%). Of the remaining 27 patients, 21 were successfully genotyped and 17/21 (81%) harboured ≥1 clinically relevant HIV-DRM. Of these, 13/17 (76.5%) had HIV-1 plasma viral loads of >1000 copies/mL. CD4 cell count <200 cells/mm(3) at the time of recruitment was independently associated with a close to 8-fold increased odds of virological failure [adjusted OR (aOR) = 7.71, 95% CI = 2.86-20.78, P < 0.001] and with a >8-fold increased odds of developing HIV-DRM (aOR = 8.46, 95% CI = 2.48-28.93, P = 0.001).\n\n\n\nHigh levels of viral suppression can be achieved in rural sub-Saharan Africa when treatment and care programmes are well managed. In the absence of routine HIV sequencing, the WHO-recommended threshold of 1000 viral RNA copies/mL largely discriminates virological failure secondary to HIV-DRM.",
"affiliations": "Ifakara Health Institute, Ifakara, United Republic of Tanzania.;Swiss Tropical and Public Health Institute, Basel, Switzerland.;Swiss Tropical and Public Health Institute, Basel, Switzerland.;University of Basel, Basel, Switzerland.;University of Basel, Basel, Switzerland.;Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.;Swiss Tropical and Public Health Institute, Basel, Switzerland.;Swiss Tropical and Public Health Institute, Basel, Switzerland.;Swiss Tropical and Public Health Institute, Basel, Switzerland.;Molecular Virology, Department Biomedicine Petersplatz, University of Basel, Basel, Switzerland.;ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.",
"authors": "Ntamatungiro|Alex J|AJ|;Muri|Lukas|L|;Glass|Tracy R|TR|;Erb|Stefan|S|;Battegay|Manuel|M|;Furrer|Hansjakob|H|;Hatz|Christoph|C|;Tanner|Marcel|M|;Felger|Ingrid|I|;Klimkait|Thomas|T|;Letang|Emilio|E|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkx095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "72(7)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019829:Nevirapine; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D012424:Rural Population; D013636:Tanzania; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2069-2074",
"pmc": null,
"pmid": "28387865",
"pubdate": "2017-07-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Strengthening HIV therapy and care in rural Tanzania affects rates of viral suppression.",
"title_normalized": "strengthening hiv therapy and care in rural tanzania affects rates of viral suppression"
} | [
{
"companynumb": "TZ-GLAXOSMITHKLINE-TZ2017111882",
"fulfillexpeditecriteria": "1",
"occurcountry": "TZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "Elucidating a medical history and gaining patient consent and buy-in are difficult in any teenager presenting to a North American pediatric emergency department, but especially so when they present with limited English fluency. Translators can make this process easier, but both limited availability and impreciseness in translation can reduce their utility. We describe 2 teenage females who presented to our pediatric emergency department within 48 hours with similar presentations but no obvious organic cause or examination findings to suggest a specific diagnosis. We demonstrate how complex language translation issues in these adolescents contributed to prolonged diagnoses and advocate for independent interpreters to be available on first presentation to hospital.",
"affiliations": "From the Departments of Pediatrics.;Pediatrics and Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;Pediatrics and Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Departments of Pediatrics.",
"authors": "Bravo|Michael|M|;Lim|Rodrick|R|;Poonai|Naveen|N|;Chen|Breanna|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "37(5)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D002648:Child; D004636:Emergency Service, Hospital; D005260:Female; D006761:Hospitals; D006801:Humans; D007802:Language; D014175:Translating",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e272-e274",
"pmc": null,
"pmid": "30130342",
"pubdate": "2021-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Suspicion and Language Translation in the Pediatric Emergency Department.",
"title_normalized": "clinical suspicion and language translation in the pediatric emergency department"
} | [
{
"companynumb": "CA-MLMSERVICE-20210526-2905021-1",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "4",
... |
{
"abstract": "In a meta-analysis of two identically designed, well-controlled, randomized, double-blind clinical trials, we compared 5 days of dirithromycin with 7 days of erythromycin for acute exacerbations of chronic bronchitis. Five hundred and thirty-one patients were randomized to receive dirithromycin (500 mg od) for 5 days and 526 patients were randomized to receive erythromycin (250 mg qid) for 7 days. Clinical and bacteriological responses were assessed 3-5 days after therapy and at termination from the study. Adverse events were collected from both groups and compared with each other, before and after treatment. Of the 690 patients clinically appraisable at the post-therapy visit, 298 (84.2%) dirithromycin-treated patients and 270 (80.4%) erythromycin-treated patients showed a favourable response. At termination, 273 (77.1%) dirithromycin-treated patients and 243 (72.3%) erythromycin-treated patients showed a favourable response. The microbiological cure was equivalent in the two groups (75% of dirithromycin-treated patients and 74.1% of erythromycin-treated patients showed a favourable response at termination). After therapy, dirithromycin was as effective as erythromycin in eradicating Streptococcus pneumoniae (77.8% vs 90.9%), Haemophilus influenzae (71.7% vs 72.2%), Moraxella catarrhalis (93.3% vs 88.9%) and Staphylococcus aureus (81.8% vs 82.1%). Although not statistically significant, fewer dirithromycin-treated patients reported adverse events than did erythromycin-treated patients. Nausea (6.8% vs 7.8%), headache (7.3% vs 8.2%) and diarrhoea (6.6% vs 9.5%) were the most frequently reported adverse events in both groups. In the treatment of acute exacerbations of chronic bronchitis, 5 days of dirithromycin is as effective as 7 days of erythromycin.",
"affiliations": "Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.",
"authors": "Wasilewski|M M|MM|;Johns|D|D|;Sides|G D|GD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; C053853:dirithromycin; D004917:Erythromycin",
"country": "England",
"delete": false,
"doi": "10.1093/jac/43.4.541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "43(4)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D001991:Bronchitis; D002648:Child; D002908:Chronic Disease; D004311:Double-Blind Method; D004917:Erythromycin; D016905:Gram-Negative Bacterial Infections; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D018942:Macrolides; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "541-8",
"pmc": null,
"pmid": "10350384",
"pubdate": "1999-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D017418:Meta-Analysis; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Five-day dirithromycin therapy is as effective as seven-day erythromycin therapy for acute exacerbations of chronic bronchitis.",
"title_normalized": "five day dirithromycin therapy is as effective as seven day erythromycin therapy for acute exacerbations of chronic bronchitis"
} | [
{
"companynumb": "US-ARBOR PHARMACEUTICALS, LLC-US-2019ARB001059",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERYTHROMYCIN"
},
"drugad... |
{
"abstract": "We present here a case of extensive necrotizing fasciitis during sorafenib treatment in a patient with HBV-related hepatocellular carcinoma. Despite emergent extensive surgical debridement, the patient's clinical status progressive worsened until interruption of sorafenib therapy. The patient was successfully treated with temporal interruption of sorafenib therapy. To our knowledge, this is the first case report of sorafenib-associated necrotizing fasciitis. Given the life-threatening nature of the infection and the necessity for urgent intervention, clinicians should be aware of this possible adverse effect of tyrosine kinase inhibitors.",
"affiliations": "Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea.;Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea.;Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea.",
"authors": "Kang|Ho Won|HW|;Yun|Seok-Joong|SJ|;Kim|Wun-Jae|WJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00611",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30122-210.1016/j.idcr.2019.e00611e00611ArticleNecrotizing fasciitis associated with sorafenib treatment Kang Ho Won abYun Seok-Joong sjyun@chungbuk.ac.krab⁎Kim Wun-Jae aba Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Koreab Department of Urology, Chungbuk National University Hospital, Cheongju, South Korea⁎ Corresponding author at: Department of Urology, College of Medicine and Institute for Tumor Research, Chungbuk National University, 776 1sunhwan-ro, Seowon-gu, Cheonju 28644, South Korea. sjyun@chungbuk.ac.kr27 7 2019 2019 27 7 2019 18 e0061115 5 2019 23 7 2019 23 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• There are only few case reports available on NF resulting from molecular targeted therapy.\n\n• This is the first case report of sorafenib-associated NF.\n\n• Clinicians should be aware of this possible adverse effect of molecular targeted therapy.\n\n\n\nWe present here a case of extensive necrotizing fasciitis during sorafenib treatment in a patient with HBV-related hepatocellular carcinoma. Despite emergent extensive surgical debridement, the patient's clinical status progressive worsened until interruption of sorafenib therapy. The patient was successfully treated with temporal interruption of sorafenib therapy. To our knowledge, this is the first case report of sorafenib-associated necrotizing fasciitis. Given the life-threatening nature of the infection and the necessity for urgent intervention, clinicians should be aware of this possible adverse effect of tyrosine kinase inhibitors.\n\nKeywords\nNecrotizing fasciitisAdverse drug reactionTyrosine kinase inhibitorsHepatocellular carcinoma\n==== Body\nIntroduction\nSorafenib, an oral tyrosine kinase inhibitor (TKI), inhibits vascular endothelial growth factor (VEGF) receptors and prevents tumor proliferation and angiogenesis [1]. Hypertension, hand–foot skin reactions, hepatotoxicity, fatigue, diarrhea and stomatitis were the most frequently observed adverse effect of treatment with VEGF-inhibitors. Impaired wound healing have been reported during TKI therapy [1,2]. Temporary interruption of TKIs therapy is recommended for precautionary reasons in patients undergoing major surgical procedures [3]. In 2013, manufacturer of bevacizumab, a monoclonal antibody to the VEGF-A ligand, alerted healthcare professionals to rare cases of necrotizing fasciitis (NF) in patients treated with bevacizumab [[4], [5], [6]]. Recently, NF during sunitinib treatment has been reported in medical literature [7]. This serious adverse drug reaction has not previously been reported in patients who has taken sorafenib. To our knowledge, this is the first case report of sorafenib-associated NF.\n\nCase report\nA 57-year-old male presented to the emergency department complaining of painful right inguinal swelling for 2 days. The patient denied any history of trauma, insect bites or allergies. His medical history revealed that a history of chronic hepatitis B virus (HBV) infection and liver cirrhosis (Child-Pugh A). He was diagnosed with HBV-related hepatocellular carcinoma. The patient was felt to be unfit for curative approach and he underwent seven sessions of transcatheter arterial chemoembolization and intensity modulated radiation therapy. He was being treated with tenofovir disoproxil fumarate 300 mg/day, and sorafenib 800 mg daily, which began 3 months before the admission. His general health of the patient was not poor, with body mass index23.9 kg/m2 and his Eastern Cooperative Oncology Group performance status score was 0.\n\nOn admission to the emergency department, the patient had a temperature of 36.5 °C, a blood pressure 92/52 mmHg, heart rate 109/min, respiratory rate 22/min, and oxygen saturation 99% on room air and was alert and oriented. After fluid hydration with 1 L normal saline, his follow-up vital signs were stable, with blood pressure 114/61 mmHg, and heart rate 95/min. Physical examination revealed marked erythema over his right lower abdomen, right inguinal area and the scrotum. The overlying skin was warm, mildly edematous, and extremely tender when palpated. No sign of crepitus was identified. Laboratory studies included a white blood cell count 11.84 × 109/L, absolute neutrophil 10.96 × 109/L, hemoglobin 14.7 gm/L, platelets 41 × 109/L. Coagulation study showed abnormal prothrombin time 18.2 s, international normalized ratio 1.56 and an activated partial thromboplastin time of 44.7 s. Inflammatory markers were elevated with a C-reactive protein of 15.96 mg/dL and a procalcitonin 7.94 ng/mL. Initial urine and blood cultures failed to reveal any organisms. Computed tomography of the lower abdomen and pelvis revealed extensive emphysema around the testicles, perineal subcutaneous tissue, and around the right lower abdomen wall (Fig. 1a).Fig. 1 (a) Computed tomography showing extensive emphysema around the lower abdominal wall, inguinal area, and scrotum. (b) Intraoperative image of the immediate surgical debridement demonstrating the extensive necrosis of the lower abdominal wall, inguinal area, and scrotum.\n\nFig. 1\n\nBased on the clinical features, diagnosis of NF was made and the patient started on empirical intravenous broad-spectrum antimicrobials combinations (ampicillin-sulbactam plus clindamycin) and later adjusted to the culture sensitivity of the microbial isolates. He underwent emergent surgical debridement under general anesthesia and all the necrotic and dead tissue was removed, leaving behind a margin of healthy looking tissue (Fig. 1b). Pus and necrotic tissue were sent for culture and sensitivity testing and showed the growth of Staphylococcus lugdunensis and susceptibility to the previously started antimicrobials. Local wound care was performed with moist gauze dressings changed daily until healthy granulation tissue was observed. Despite emergent extensive surgical debridement, the patient's clinical status progressive worsened until the interruption of sorafenib therapy. The infection gradually subsided, the Fournier’s gangrene resolved completely, and good granulation was present one week after interruption of sorafenib therapy. Secondary closure of the wound was performed on hospital day 14. The subcutaneous air completely disappeared on abdominal CT and the patient was finally discharged on the 23rd postoperative day.\n\nDiscussion\nNF is a life-threatening infection, with reported mortality rates ranging from 8.7% to 73% (mean 32.2%) [8]. There are several risk factors for this condition, the most recognizable being immunodeficiency, diabetes, obesity, and alcohol abuse [9]. Rarely, NF can develop related to all-trans-retinoic acid, bisphosphonates, and radiotherapy [8]. In addition, several reports have shown that liver cirrhosis is a common underlying disease in patients with NF [10]. Liver cirrhosis can weaken the intestinal-portal route barrier, which facilitates the entry of bacteria into the systemic circulation and renders patients prone to various infectious diseases [10]. This patient had a several predisposing comorbidity factors which can be a predispose causes of NF, such as liver cirrhosis, malignancy and history of radiation. Therefore, sorafenib was determined to be the “possible cause”, not “probable cause” of the necrotizing fasciitis according to the Naranjo Adverse Drug Reaction Probability Scale (+4), and WHO-UMC causality categories [11,12].\n\nThere are only few case reports available on necrotizing fasciitis resulting from molecular targeted therapy. NF has been reported in patients receiving bevacizumab in both clinical trials and in the post-marketing setting [5,6,13,14]. A case report by Piszczek et al. described a case of sunitinib-related NF [7]. This serious adverse drug reaction had not previously been reported in patients who were taken sorafenib. Given the common pathophysiologic mechanism of skin toxicity in patients who treated with molecular targeted therapy is subcutaneous artery thrombosis leading to tissue hypoxia, necrosis, and increased susceptibility to invasion by pathogenic and opportunistic bacteria, sorafenib also might be a risk factor for this rare but fatal complication [7,14].\n\nHung et al. described the first case of necrotizing fasciitis jointly associated with the microbes Group B Streptococcus and S. lugdunensis [15]. S. lugdunensis is a coagulase-negative Staphylococcus with a pathogenicity and virulence more similar to Staphylococcus aureus than to other coagulase-negative Staphylococcus spp. [15,16]. These organisms are frequently misidentified as S. aureus because of their morphologic appearance with yellow pigmentation and complete hemolysis when cultured on blood agar [15,17,18]. Even so, appropriate identification of S. lugdunensis is imperative as misidentification may result in inadequately treated, prolonged, and persistent infection [15,18].\n\nBesides initial administration of broad-spectrum antimicrobials, urgent and aggressive surgical intervention, often comprising multiple debridement procedures before eventual definitive reconstruction, is required [4,19]. Auxiliary measures can also be implemented, such as negative pressure wound therapy (NPWT) or hyperbaric oxygenation [19]. We did not use NPWT or hyperbaric oxygenation therapy in this patient. We performed only daily saline irrigation and povidone soaked gauze application by being sealed with a waterproof film to protect local wound infection and fecal contamination. Secondary closure of the wound was also performed without skin graft or flaps. Nevertheless, the late recognition of sorafenib taking resulted in more requirement of additional debridement and prolongation of hospital stay.\n\nFunding\nThe research was supported by the International Science and Business Belt Program through the Ministry of Science, ICT and Future Planning (2015-DD-RD-0070)\n\nEthics statement\nThe protocol of the present study was reviewed and approved by the Institutional Review Board (IRB) of our hospital (IRB No. 2019-03-011). The patient provided written informed consent.\n\nAuthorship contribution\nHo Won Kang: Conception and design of study, acquisition of data, drafting the manuscript.\n\nSeok-Joong Yun: Conception and design of study, revising the manuscript critically for important intellectual content.\n\nWun-Jae Kim: revising the manuscript critically for important intellectual content.\n\nDeclaration of Competing Interest\nNone of the authors has a conflict of interest.\n==== Refs\nReferences\n1 Randrup Hansen C. Grimm D. Bauer J. Wehland M. Magnusson N.E. Effects and side effects of using sorafenib and sunitinib in the treatment of metastatic renal cell carcinoma Int J Mol Sci 18 2017 \n2 Lee W.J. Lee J.L. Chang S.E. Lee M.W. Kang Y.K. Choi J.H. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib Br J Dermatol 161 2009 1045 1051 19558553 \n3 Shah D.R. Dholakia S. Shah R.R. Effect of tyrosine kinase inhibitors on wound healing and tissue repair: implications for surgery in cancer patients Drug Saf 37 2014 135 149 24526268 \n4 Biondi L. Safety information on AVASTIN (bevacizumab) 1452 2013 18 Internet Document: 2 May 2013. Available from: URL: http://healthycanadians. gc. ca803086880. Reactions \n5 Şendur M.A.N. Aksoy S. Özdemir N.Y. Zengin N. Necrotizing fasciitis secondary to bevacizumab treatment for metastatic rectal adenocarcinoma Indian J Pharmacol 46 2014 125 24550600 \n6 Wong J. Bevacizumab is linked to cases of necrotising fasciitis Lancet Oncol 14 2013 e259 \n7 Piszczek J. Dalton B. Peters T. Ruether D. Urbanski S. Extensive necrotizing fasciitis associated with sunitinib therapy Clin Genitourin Cancer 12 2014 e47 e49 24445249 \n8 Roje Z. Roje Z. Matic D. Librenjak D. Dokuzovic S. Varvodic J. Necrotizing fasciitis: literature review of contemporary strategies for diagnosing and management with three case reports: torso, abdominal wall, upper and lower limbs World J Emerg Surg 6 2011 46 22196774 \n9 Harrington D.H. Lenahan C.M. Sanders R.M. A practitioner’s guide to necrotizing fasciitis Nurse Pr 40 2015 45 48 \n10 Hung T.H. Tsai C.C. Tsai C.C. Tseng C.W. Hsieh Y.H. Liver cirrhosis as a real risk factor for necrotising fasciitis: a three-year population-based follow-up study Singapore Med J 55 2014 378 382 25091887 \n11 Belhekar M.N. Taur S.R. Munshi R.P. A study of agreement between the Naranjo algorithm and WHO-UMC criteria for causality assessment of adverse drug reactions Indian J Pharmacol 46 2014 117 120 24550597 \n12 Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 1981 239 245 7249508 \n13 Gamboa E.O. Rehmus E.H. Haller N. Fournier’s gangrene as a possible side effect of bevacizumab therapy for resected colorectal cancer Clin Colorectal Cancer 9 2010 55 58 20100690 \n14 Ugai T. Norizuki M. Mikawa T. Ohji G. Yaegashi M. Necrotizing fasciitis caused by Haemophilus influenzae type b in a patient with rectal cancer treated with combined bevacizumab and chemotherapy: a case report BMC Infect Dis 14 2014 198 24725844 \n15 Hung T. Zaghi S. Yousefzadeh J. Leibowitz M. Necrotizing fasciitis associated with Staphylococcus lugdunensis Case Rep Infect Dis 2012 2012 \n16 Anguera I. Del Rio A. Miro J.M. Matinez-Lacasa X. Marco F. Gumá J.R. Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles Heart 91 2005 e10–e10 \n17 Herchline T.E. Ayers L.W. Occurrence of Staphylococcus lugdunensis in consecutive clinical cultures and relationship of isolation to infection J Clin Microbiol 29 1991 419 421 2037657 \n18 Seifert H. Oltmanns D. Becker K. Wisplinghoff H. Von Eiff C. Staphylococcus lugdunensis pacemaker-related infection Emerg Infect Dis 11 2005 1283 16102320 \n19 Sarani B. Strong M. Pascual J. Schwab C.W. Necrotizing fasciitis: current concepts and review of the literature J Am Coll Surg 208 2009 279 288 19228540\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Adverse drug reaction; Hepatocellular carcinoma; Necrotizing fasciitis; Tyrosine kinase inhibitors",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00611",
"pmc": null,
"pmid": "31428562",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "24725844;24445249;22675644;28230776;7249508;24550600;16102320;22196774;24550597;19558553;24526268;15657200;25091887;19228540;25710244;20100690;2037657",
"title": "Necrotizing fasciitis associated with sorafenib treatment.",
"title_normalized": "necrotizing fasciitis associated with sorafenib treatment"
} | [
{
"companynumb": "KR-BAYER-2019-154080",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL"
},
"drugadditional": null,
... |
{
"abstract": "Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.\n\n\n\nAdult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.\n\n\n\n20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).\n\n\n\nThe RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.\n\n\n\nBill and Melinda Gates Foundation, South African Medical Research Council.",
"affiliations": "South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;TB Modelling Group, TB Centre, Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.;TB Modelling Group, TB Centre, Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;The Aurum Institute, Johannesburg, South Africa.;The Aurum Institute, Johannesburg, South Africa.;DST/NRF Centre of Excellence for Biomedical TB Research and South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa.;DST/NRF Centre of Excellence for Biomedical TB Research and South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.;DST/NRF Centre of Excellence for Biomedical TB Research and South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.;The Aurum Institute, Johannesburg, South Africa; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa. Electronic address: mark.hatherill@uct.ac.za.",
"authors": "Scriba|Thomas J|TJ|;Fiore-Gartland|Andrew|A|;Penn-Nicholson|Adam|A|;Mulenga|Humphrey|H|;Kimbung Mbandi|Stanley|S|;Borate|Bhavesh|B|;Mendelsohn|Simon C|SC|;Hadley|Katie|K|;Hikuam|Chris|C|;Kaskar|Masooda|M|;Musvosvi|Munyaradzi|M|;Bilek|Nicole|N|;Self|Steven|S|;Sumner|Tom|T|;White|Richard G|RG|;Erasmus|Mzwandile|M|;Jaxa|Lungisa|L|;Raphela|Rodney|R|;Innes|Craig|C|;Brumskine|William|W|;Hiemstra|Andriëtte|A|;Malherbe|Stephanus T|ST|;Hassan-Moosa|Razia|R|;Tameris|Michèle|M|;Walzl|Gerhard|G|;Naidoo|Kogieleum|K|;Churchyard|Gavin|G|;Hatherill|Mark|M|;|||",
"chemical_list": "D000995:Antitubercular Agents; D015415:Biomarkers; D012329:RNA, Bacterial; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine",
"country": "United States",
"delete": false,
"doi": "10.1016/S1473-3099(20)30914-2",
"fulltext": "\n==== Front\nLancet Infect Dis\nLancet Infect Dis\nThe Lancet. Infectious Diseases\n1473-3099 1474-4457 Elsevier Science ;, The Lancet Pub. Group \n\nS1473-3099(20)30914-2\n10.1016/S1473-3099(20)30914-2\nArticles\nBiomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial\nScriba Thomas J PhDa Fiore-Gartland Andrew PhDb† Penn-Nicholson Adam PhDa Mulenga Humphrey MPHa Kimbung Mbandi Stanley PhDa Borate Bhavesh MSb Mendelsohn Simon C MBChBa Hadley Katie PhDa Hikuam Chris PhDa Kaskar Masooda MBAa Musvosvi Munyaradzi PhDa Bilek Nicole PhDa Self Steven PhDb Sumner Tom PhDc White Richard G PhDc Erasmus Mzwandile MSca Jaxa Lungisa BTecha Raphela Rodney BSc[Hons]a Innes Craig MBChBd Brumskine William MBChBd Hiemstra Andriëtte MBChBe Malherbe Stephanus T MBChBe Hassan-Moosa Razia MPHfg Tameris Michèle MBChBa Walzl Gerhard MBChBe Naidoo Kogieleum PhDfg Churchyard Gavin MBBChdh Hatherill Mark MDmark.hatherill@uct.ac.zaa* CORTIS-01 Study TeamBaepanye Kesenogile Baepanye Tshepiso Clarke Ken Collignon Marelize Dlamini Audrey Eyre Candice Feni Tebogo Fikizolo Moogo Galane Phinda Goliath Thelma Gangat Alia Malefo-Grootboom Shirley Janse van Rensburg Elba Janse van Rensburg Bonita Kekana Sophy Zietsman Marietjie Kock Adrianne Kunene Israel Lakhi Aneessa Langa Nondumiso Ledwaba Hilda Luphoko Marillyn Mabasa Immaculate Mabe Dorah Mabuza Nkosinathi Majola Molly Makhetha Mantai Makoanyane Mpho Makhubalo Blossom Malay Vernon Market Juanita Matshego Selvy Mbipa Nontsikelelo Mmotsa Tsiamo Modipa Sylvester Mopati Samuel Moswegu Palesa Mothaga Primrose Muller Dorothy Nchwe Grace Nel Maryna Nhlangulela Lindiwe Ntamo Bantubonke Ntoahae Lawerence Ntshauba Tedrius Sanyaka Nomsa Seabela Letlhogonolo Selepe Pearl Senne Melissa Serake MG Thlapi Maria Tshikovhi Vincent Tswaile Lebogang van Aswegen Amanda Mbata Lungile Takavamanya Constance Pinho Pedro Mdlulu John Taljaard Marthinette Slabbert Naydene Sayed Sharfuddin Nielson Tanya Senne Melissa Ni Sein Ni Mbata Lungile Govender Dhineshree Chinappa Tilagavathy Zulu Mbali Ignatia Maphanga Nonhle Bridgette Hlathi Senzo Ralph Gumede Goodness Khanyisile Shezi Thandiwe Yvonne Maphanga Jabulisiwe Lethabo Jali Zandile Patrica Cwele Thobelani Gwamanda Nonhlanhla Zanele Elsie Dlamini Celaphiwe Sing Zibuyile Phindile Penlee Ntanjana Ntombozuko Gloria Nzimande Sphelele Simo Mbatha Siyabonga Maharaj Bhavna Moosa Atika Corris Cara-Mia Kafaar Fazlin Geldenhuys Hennie Luabeya Angelique Kany Kany Shenje Justin Botes Natasja Rossouw Susan Africa Hadn Diamond Bongani Braaf Samentra Stryers Sonia Carstens Alida Jansen Ruwiyda Mabwe Simbarashe Mulenga Humphrey Herling Roxane Veldsman Ashley Makhete Lebohgang Steyn Marcia Buhlungu Sivuyile Erasmus Margareth Davids Ilse Plaatjie Patiswa Companie Alessandro Ratangee Frances Veldtsman Helen Petersen Christel Abrahams Charmaine Moses Miriam Kelepu Xoliswa Gregg Yolande Swanepoel Liticia Magawu Nomsitho Cetywayo Nompumelelo Mactavie Lauren Valley Habibullah Filander Elizabeth Nqakala Nambitha Maasdorp Elizna Khoury Justine Kriel Belinda Smith Bronwyn Muller Liesel Tonsing Susanne Loxton Andre Hiemstra Andriette Ahlers Petri Flinn Marika Chung Eva Chung Michelle Sato Alicia a South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa\nb Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA\nc TB Modelling Group, TB Centre, Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK\nd The Aurum Institute, Johannesburg, South Africa\ne DST/NRF Centre of Excellence for Biomedical TB Research and South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa\nf Centre for the AIDS Programme of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa\ng MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa\nh School of Public Health, University of Witwatersrand, Johannesburg, South Africa\n* Correspondence to: Prof Mark Hatherill, South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, 7925, South Africa mark.hatherill@uct.ac.za† Contributed equally\n\n\n1 3 2021 \n3 2021 \n21 3 354 365\n© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license2021This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Summary\nBackground\nTargeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.\n\nMethods\nAdult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.\n\nFindings\n20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25–6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI −145 to 65).\n\nInterpretation\nThe RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.\n\nFunding\nBill and Melinda Gates Foundation, South African Medical Research Council.\n==== Body\nIntroduction\nLarge-scale prevention of progression from Mycobacterium tuberculosis infection to tuberculosis disease is key to achieving WHO End TB Strategy targets, yet tuberculin skin tests (TST) and interferon (IFN) γ release assays have poor specificity for incident tuberculosis.1 A biomarker-targeted prevention strategy using a highly specific correlate of risk (COR) for incident tuberculosis, in tandem with effective short-course tuberculosis preventive therapy (TPT),2 might impact the epidemic by preventing incident tuberculosis disease before transmission.3 Modelling suggests a three-times reduction in burden of TPT if targeted by COR, compared with IFNγ release assays and TST.4 Furthermore, because active tuberculosis disease should be excluded before starting TPT, additional utility of the prognostic COR as a screening (triage) test to identify undiagnosed tuberculosis disease would allow earlier curative treatment. WHO and FIND have developed target product profiles (TPP) for triage tests for tuberculosis (optimal and minimum sensitivity of >95% and >90%, and specificity of >80% and >70%, respectively),5 and incipient tuberculosis tests (minimum sensitivity and specificity of 75% and 75%, and optimal sensitivity and specificity of 90% and 90%, respectively).6\n\nResearch in context\nEvidence before this study\n\nHost blood RNA signatures have potential as tuberculosis triage or diagnostic tests, and as predictive tests to target tuberculosis preventive therapy. We searched MEDLINE, Scopus, Web of Science, and EBSCO libraries for publications between Jan 1, 2005, and May 31, 2020, using the search terms “Tuberculosis” OR “TB” OR “Mycobacterium tuberculosis” OR “MTB” AND “diagnosis” OR “diagnostic” OR “detect” OR “predic”OR “prognosis” OR “prognostic” OR “screen” AND “Blood Biomarker” OR “blood biomarkers” OR “bio-signature” OR “gene expression” OR “genetic transcription” OR “host blood” OR “immune marker” OR “immunologic marker” OR “Ribonucleic Acid” OR “RNA” OR “signature” OR “surrogate endpoint” OR “surrogate marker” OR “transcriptome” OR “transcriptomic” AND “Area under curve” OR “AUC” OR “receiver operating characteristic” OR “ROC” OR “Accuracy” OR “Performance” OR “sensitivity” OR “specificity”. Studies comparing blood RNA signatures in individuals with tuberculosis versus Mycobacterium tuberculosis-uninfected controls, individuals with other respiratory diseases, or with M tuberculosis infection and using a microbiological reference standard of either sputum M tuberculosis culture, Xpert MTB/RIF, or smear microscopy for tuberculosis diagnosis, were included.\n\n28 studies reported evaluation of 32 host blood RNA signatures for diagnosis or prediction of progression to tuberculosis disease in 83 cohorts. Only two studies prospectively tested performance of an RNA signature in all evaluable participants; the remainder used a case-control design. Multiple studies have tested tuberculosis preventive therapy in people with M tuberculosis latent tuberculosis infection. No studies have tested efficacy of tuberculosis preventive therapy to avert disease in RNA signature-positive people.\n\nAdded value of this study\n\nThis large randomised, controlled trial in five South African communities prospectively tested diagnostic and prognostic performance of an RNA signature (RISK11) in all evaluable participants, and estimated efficacy of tuberculosis preventive therapy to avert disease in RNA signature-positive people. More than 1% of HIV-uninfected community volunteers had previously undiagnosed, microbiologically confirmed tuberculosis at screening, more than 80% of which was asymptomatic. RISK11 showed moderate performance for tuberculosis triage, but good performance for diagnosis of symptomatic tuberculosis, and for short-term prediction of incident tuberculosis. 3 months of once-weekly, high-dose isoniazid and rifapentine (3HP) did not reduce incident disease in RISK11-positive individuals over 15 months of follow-up.\n\nImplications of all the available evidence\n\nHost blood biomarker development must consider that subclinical tuberculosis might be characterised by more heterogenous, or less pronounced blood inflammatory responses than symptomatic tuberculosis, or both, which will affect RNA signature performance. RISK11 might be better suited to screening of symptomatic individuals with possible tuberculosis than for mass community-based screening. RISK11 can identify those at highest risk for short-term progression to disease, but a more potent regimen than 3HP might be needed to prevent tuberculosis in RISK11-positive individuals.\n\n\n\nWe previously developed a 16-gene transcriptomic signature by whole blood RNA sequencing for identification of individuals at high risk of developing tuberculosis (the Zak16 signature).7, 8 Measurement of Zak16 was adapted to quantitative RT-PCR (RT-qPCR), and predictive ability for incident tuberculosis was validated in an independent longitudinal cohort of household contacts of tuberculosis patients.8 We reduced this signature to 11 genes (RISK11) with equivalent performance,9, 10 to allow testing in 96-well PCR format. Zak16 and RISK11 also did well as non-sputum screening tests for prevalent, active tuberculosis in case-control studies, measured by RNA sequencing, microarray,7, 8 or microfluidic RT-qPCR.9, 10 In a 2020 systematic review and patient-level pooled meta-analysis of 17 transcriptomic signatures for prognosis of incident tuberculosis, Zak16 was among eight signatures that achieved a positive predictive value above the WHO TPP benchmark for incipient tuberculosis tests.11 Since case-control studies might overestimate performance characteristics, testing in unselected populations is needed.\n\nWe report on a randomised controlled trial (CORTIS; NCT02735590), which prospectively measured diagnostic and prognostic performance of RISK11 for triage of prevalent and prediction of incident tuberculosis in South African adults; and, in parallel, estimated efficacy of short-course TPT to avert incident disease in RISK11-positive individuals.\n\nMethods\nStudy design\nThis randomised controlled trial used a hybrid treatment selection, three-group study design to evaluate efficacy of the intervention and, in parallel, performance of the biomarker used to allocate that intervention (figure 1).2 The coprimary aims were to test, over 15 months, whether RISK11 status differentiates between people with and without cumulative prevalent or incident tuberculosis; and whether preventive therapy (weekly high-dose isoniazid and rifapentine for 12 weeks [3HP]) reduces tuberculosis incidence among RISK11-positive people compared with active surveillance only. RISK11 performance to detect prevalent tuberculosis was evaluated in all groups at baseline. RISK11 performance to predict incident tuberculosis was evaluated in the untreated RISK11-positive and RISK11-negative groups, and treatment efficacy was estimated from the 3HP treated and untreated RISK11-positive groups, after omitting participants with baseline tuberculosis. Efficiency of the hybrid study design was maximised by using the RISK11-positive and 3HP-negative group to evaluate both biomarker performance and treatment efficacy.Figure 1 Study design\n\nThe prevalence of RISK11 positivity was not precisely known in the study population; therefore, the number of individuals to be screened and the randomisation of RISK11-negative participants to enrolment was monitored and adjusted adaptively to ensure concurrent enrolment of the target number of RISK11-positive and RISK11-negative participants, per protocol specifications. The study used a three-group design to evaluate efficacy of the intervention and, in parallel, performance of the biomarker used to allocate that intervention. Diagnostic performance for differentiation of prevalent tuberculosis was tested in all three groups at baseline; prognostic performance for differentiation of incident tuberculosis over 15 months was tested in the two untreated groups (untreated RISK11 positive and untreated RISK11 negative); and treatment efficacy of 3HP over 15 months was tested in the two RISK11-positive groups (treated and untreated RISK11 positive). *Participants evaluated for eligibility at screening and enrolment. †Groups randomly assigned in blocks to ensure concurrent enrolment.\n\n\n\nRoutine implementation of TPT requires that patients are screened to exclude prevalent tuberculosis before TPT is provided to prevent incident disease. Therefore, because risk for prevalent and incident tuberculosis by RISK11 status must be understood before efficacy of preventive therapy against incident tuberculosis in RISK11-positive people can be interpreted, these secondary analyses are presented before the primary analysis of treatment efficacy.\n\nThe trial protocol (appendix p 21) was approved by the South African Health Products Regulatory Agency (20160305) by the Institutional Human Ethics Committees of participating sites; and was registered on ClinicalTrials.gov (NCT02735590). All participants provided written informed consent in their language of choice.\n\nParticipants\nAdult volunteers living in tuberculosis-endemic communities in South Africa were recruited at five sites (South African Tuberculosis Vaccine Initiative, Worcester; Immunology Research Group, Stellenbosch University, Ravensmead; Aurum Institute, Klerksdorp and Rustenberg; and Centre for the AIDS Programme of Research in South Africa, Durban). Community-based recruitment was by word-of-mouth, house-to-house visits, and liaison with non-governmental organisations. Recruitment did not target groups at high risk of tuberculosis, such as household contacts. Eligible participants were aged between 18 years and 59 years, HIV-negative, without a history of tuberculosis disease in the last 3 years or preselected comorbidities (appendix p 8).\n\nScreening\nVenous blood was collected in PAXgene RNA tubes from all potentially eligible people at screening, frozen at −20°C, and shipped weekly to the South African Tuberculosis Vaccine Initiative Immunology Laboratory for RISK11 testing by qRT-PCR assay. Participants with a RISK11 score of at least 60% were classified a priori as RISK11 positive and less than 60% as RISK11 negative. This 60% threshold was the optimal point at which sensitivity and specificity for prognosis of incident tuberculosis were balanced in case-control studies.2 Samples with failed reference primer-probe reactions, with marked deviation in internal positive control sample from historical runs, or more than 30% failed interferon-stimulated genes primer-probe reactions (see quality control criteria and analysis script in Bitbucket instance) were classified as indeterminate. Per-participant qualitative results (RISK11 positive and RISK11 negative) were provided to the Triclinium Clinical Development (TCD) Data Centre for participant randomisation (see appendix pp 2–3).\n\nRandomisation and masking\nAssignment to study group was managed by an unmasked randomisation team from the TCD Data Centre, based on RISK11 status. RISK11-positive volunteers were randomly assigned (1:2; block size 15) to either open-label 3HP (3HP-positive group), or active tuberculosis surveillance without 3HP (3HP-negative group), in accordance with a randomisation schedule generated using SAS, version 9.4. RISK11-negative volunteers were concurrently randomly assigned either to active tuberculosis surveillance (3HP-negative group) or to non-participation, to enrich the study population for RISK11-positive participants.\n\nStudy group allocation was revealed to site staff after enrolment of eligible participants within 28 days of screening. The 3HP-negative group was double-blinded to RISK11 status, but unblinded to treatment allocation; the 3HP-positive group was unblinded to both RISK11-positive status and treatment allocation (figure 1). RISK11-positive participants randomly assigned to active surveillance did not receive a placebo, to maintain blinding of participants and study team members to RISK11 status.\n\nProcedures\nTarget enrolment was maximally 3200 participants (1500 RISK11 positive and 1700 RISK11 negative). The randomisation ratio for RISK11-negative volunteers was adapted to ensure concurrent enrolment of the recruitment target. Adaptations occurred at intervals, informed by 3-monthly operational monitoring reports based on enrolment rate, RISK11-positive and RISK11-negative prevalence, and tuberculosis case accrual blinded to RISK11 status (appendix p 7).\n\nEnrolment procedures included phlebotomy for IFNγ release assays (QuantiFERON TB Gold-Plus, Qiagen), tuberculosis symptom screen (a positive tuberculosis symptom screen included one or more symptoms of persistent unexplained cough, fever, night sweats, weight loss, or any haemoptysis), and collection of two spontaneous expectorated sputum samples for Xpert MTB/RIF assay (Cepheid) from all sputum-productive participants, regardless of symptoms.\n\nAll participants attended up to seven study visits, including four study site visits at months 3, 6, 12, and 15 (end of study), and three telephonic contact or field visits at months 1, 2, and 9. HIV testing was repeated at months 6 and 12.\n\nParticipants in the 3HP group received open-label, high-dose isoniazid (15 mg/kg; maximum dose 900 mg) with pyridoxine supplementation (25 mg) and rifapentine based on body weight (>32–50 kg, 750 mg; >50 kg, 900 mg), given weekly as directly observed oral doses, ideally with food, over 12 weeks. Completion of 3HP treatment was defined as receipt of 11 doses within 16 weeks (appendix p 3).\n\nOutcomes\nThe two primary outcome measures were RISK11-positive to RISK11-negative risk ratio (RR) for prevalent or incident tuberculosis disease, and 3HP treatment efficacy through 15 months. Diagnostic performance for prevalent tuberculosis was evaluated on the presence of tuberculosis at the enrolment visit within the ITT cohort.\n\nParticipants in the 3HP group had each dose directly observed by study staff, and attended clinic for evaluation of solicited adverse events and possible adverse events of special interest at weeks 1–11. Solicited adverse events included gastrointestinal signs and symptoms suggestive of hepatotoxicity, such as nausea, vomiting, and jaundice. Possible hypersensitivity reactions, including influenza-like illness, were reported as adverse events of special interest. Safety events meeting the definition for a serious adverse event, whether deemed related or unrelated to study drug, were reported for both all participants through end of study.\n\nStatistical analysis\nThe intention-to-treat (ITT) cohort included all enrolled participants who completed investigation for tuberculosis endpoints at baseline. The modified intention-to-treat (mITT) cohort included all participants in the ITT population who completed at least one post-baseline tuberculosis endpoint investigation and omitted participants with endpoint-defined tuberculosis disease at baseline (prevalent tuberculosis).\n\nThe diagnostic RR was estimated as a proportion of participants with tuberculosis disease among RISK11-positive divided by RISK11-negative participants. Prognostic performance for incident tuberculosis after enrolment was evaluated among 3HP-negative participants within the mITT cohort (ie, excluding participants with tuberculosis at baseline). Prognostic RR was estimated as the cumulative incidence through 15 months for RISK11-positive divided by RISK11-negative participants. The primary RR was an estimate of the probability of having prevalent tuberculosis or developing incident tuberculosis among RISK11-positive divided by RISK11-negative participants; this combined probability of prevalent and incident tuberculosis was computed for each group as the probability of prevalent tuberculosis plus the probability of incident tuberculosis through 15 months (conditioned on not having prevalent tuberculosis). Efficacy of 3HP preventive therapy to reduce the rate of incident tuberculosis disease compared with the untreated RISK11-positive participants was also evaluated in the mITT population. Treatment efficacy was estimated as one minus the cumulative incidence of RISK11-positive and 3HP-positive participants divided by RISK11-positive and 3HP-negative participants through 15 months. A per-protocol analysis of treatment efficacy was done and excluded RISK11-positive and 3HP-positive participants that received less than 11 of the 12 weekly doses of 3HP.\n\nFor statistical efficiency, a random subset of RISK11-negative participants were enrolled, therefore creating an ITT cohort artificially enriched with RISK11-positive participants. Therefore, unless stated otherwise, all analyses were adjusted so that results reflected the screened population. Secondary performance metrics such as sensitivity and specificity were estimated using standard formulas with binary endpoints; a percentile bootstrap with 20 000 samples was used to estimate 95% CIs. For descriptive analyses (Table 1, Table 2), rank-based Wilcoxon rank-sum tests were used to compare continuous variables in RISK11-positive versus RISK11-negative groups. Fisher's exact test was used to compare binary readouts; p values in Table 1, Table 2 were not adjusted for multiple comparisons. The prespecified statistical analysis plan is included in the appendix (p 82) and contains detailed description of the statistical methods.Table 1 Baseline characteristics and primary tuberculosis endpoints by group\n\n\tTotal (n=2923)\tRISK11 positive and\t3HP positive (n=375)\tRISK11 positive and 3HP negative (n=764)\tRISK11 negative (n=1784)\tRISK11 positive vs RISK11 negative, p value*\t\nSex\t\n\tFemale\t1585 (54·2%)\t213 (56·8%)\t469 (61·4%)\t903 (50·6%)\t<0·001\t\n\tMale\t1338 (45·8%)\t162 (43·2%)\t295 (38·6%)\t881 (49·4%)\t..\t\nAge, years\t28·5 (9·0)\t28·8 (9·5)\t28·4 (9·2)\t28·4 (8·7)\t0·541\t\nRace or ethnicity\t\n\tAsian\t4 (0·1%)\t0\t1 (0·1%)\t3 (0·2%)\t0·567\t\n\tBlack African\t1947 (66·6%)\t227 (60·5%)\t477 (62·4%)\t1243 (69·7%)\t<0·001\t\n\tWhite\t4 (0·1%)\t0\t1 (0·1%)\t3 (0·2%)\t0·567\t\n\tMixed race\t968 (33·1%)\t148 (39·5%)\t285 (37·3%)\t535 (30·0%)\t<0·001\t\nBody-mass index, kg/m2\t24·6 (7·7)\t24·1 (6·3)\t24·4 (6·1)\t24·9 (8·6)\t0·354\t\nPrevious tuberculosis\t230 (7·9%)\t36 (9·6%)\t75 (9·8%)\t119 (6·7%)\t0·003\t\nSmoking\t1478 (50·6%)\t203 (54·1%)\t391 (51·2%)\t884 (49·6%)\t0·170\t\nFamily tuberculosis history\t462 (15·8%)\t66 (17·6%)\t110 (14·4%)\t286 (16·0%)\t0·675\t\nInterferon γ release assay positive\t1895 (64·8%)\t250 (66·7%)\t528 (69·1%)\t1117 (62·6%)\t<0·001\t\nFollow-up, months\t15 (9·4–15·0)\t15 (11·1–15·0)\t15 (9·1–15·0)\t13·6 (9·4–15·0)\t0·056\t\nPrevalent tuberculosis, n (probability, 95% CI)\t61 (1·1%, 0·77–1·6)†\t47 (4·1%, 3·1–5·4)‡\t47 (4·1%, 3·1–5·4)§\t14 (0·78%, 0·47–1·3)\tNA\t\nIncident tuberculosis, n (cases per 100 person years, 95% CI)\t24 (1·05, 0·59–1·5)§\t6 (1·9, 0·35–3·5)\t14 (2·09, 0·97–3·19)\t10 (0·80, 0·30–1·30)\tNA\t\nCumulative tuberculosis, n (probability, 95% CI)¶\t85 (0·022, 0·016–0·028)†\t61 (0·066, 0·049–0·084)‖**\t61 (0·066, 0·049–0·084)**\t24 (0·018, 0·011–0·026)\tNA\t\nData are n (%), mean (SD), or median (IQR), unless stated otherwise. Secondary tuberculosis endpoints by group are in the appendix (p 13). NA=not applicable.\n\n* For continuous data, p values from Wilcoxon rank sum test. For categorical data, p values from Fischer's exact test.\n\n† Overall rate estimates are weighted combinations of the enrolled participants to reflect the screened population.\n\n‡ Overall incidence and cumulative tuberculosis excludes RISK11-positive and 3HP-positive incident cases.\n\n§ Prevalent tuberculosis among RISK11 positive was assessed by combining the 3HP-negative and 3HP-positive groups. Value is repeated for RISK11 positive and 3HP positive, and RISK11 positive and 3HP negative.\n\n¶ Probability of observing prevalent or incident tuberculosis over 15 months.\n\n‖ Probability of prevalent or incident tuberculosis not estimated for RISK11-positive and 3HP-positive because it would combine data from before and after 3HP treatment and is therefore potentially misleading.\n\n** Estimate for RISK11 positive includes 3HP-positive prevalent cases and 3HP-negative prevalent and incident cases. Value is repeated for RISK11 positive and 3HP positive, and RISK11 positive and 3HP negative.\n\nTable 2 Performance of RISK11 and IGRA for prevalent and incident tuberculosis\n\n\tPrevalent tuberculosis (ITT cohort)\tIncident tuberculosis (mITT cohort)*\t\n\tRISK11 (60)†\tRISK11 (26)†\tIGRA\tRISK11 (60)†\tRISK11 (26)†\tIGRA\t\nRisk ratio\t5·13 (2·93 to 9·43)\t7·39 (3·46 to 25·69)\t4·43 (1·93 to 14·18)\t2·61 (1·15 to 5·94)\t2·67 (1·04 to 8·66)\t2·83 (0·95 to 99·79)\t\nBiomarker prevalence\t9·2% (9·2 to 9·2)\t25·8% (24·1 to 27·4)\t63·4% (61·3 to 65·4)\t9·0% (9·0 to 9·0)\t25·3% (23·7 to 26·9)\t63·2% (61·1 to 65·3)\t\nAUC‡\t0·77 (0·68 to 0·86)\t..\t0·66 (0·58 to 0·73)\t0·63 (0·47 to 0·80)\t..\t0·67 (0·54 to 0·79)\t\nSensitivity\t34·9% (23·7 to 52·2)\t72·1% (54·5 to 90·2)\t88·7% (77·1 to 96·4)\t25·0% (12·7 to 45·9)\t47·5% (25·9 to 75·0)\t83·2% (61·9 to 100·0)\t\nSpecificity\t91·0% (90·9 to 91·1)\t74·7% (73·1 to 76·4)\t36·9% (34·9 to 39·0)\t91·1% (91·0 to 91·2)\t74·9% (73·2 to 76·5)\t37·0% (34·9 to 39·1)\t\nPPV§\t4·1% (3·0 to 5·4)\t3·1% (2·0 to 4·3)\t1·5% (1·0 to 2·2)\t1·9% (0·9 to 3·0)\t1·3% (0·6 to 2·1)\t0·9% (0·5 to 1·4)\t\nPPV (2% incidence)¶\t..\t..\t..\t6·7% (3·5 to 11·8)\t4·6% (2·5 to 7·1)\t3·3% (2·5 to 3·9)\t\nNPV§\t99·2% (98·8 to 99·6)\t99·6% (99·2 to 99·9)\t99·7% (99·3 to 99·9)\t99·4% (99·0 to 99·8)\t99·5% (99·1 to 99·9)\t99·7% (99·2 to 100·0)\t\nNPV (2% incidence)¶\t..\t..\t..\t97·9% (97·6 to 98·5)\t98·2% (97·5 to 99·2)\t98·8% (97·4 to 100·0)\t\nNNS or NNT‖\t29·9 (21·8 to 46·6)\t37·8 (25·5 to 65·7)\t83·1 (53·2 to 179·8)\t75·1 (40·4 to 277·5)\t123·8 (47·2 to 834·1)\t168 (−440 to 1059)\t\nData are risk ratio (95 %CI), % (95% CI), AUC (95% CI), or NNS or NNT (95% CI). ITT=intention to treat. mITT=modified intention-to-treat. IGRA=interferon γ release assay. AUC=area under the receiver operating characteristic curve. PPV=positive predictive value. NPV=negative predictive value. NNS=number needed to screen. NNT=number needed to treat.\n\n* Computed over 15-month prognostic window. Performance of RISK11 and IGRA for incident tuberculosis over 6-month and 12-month prognostic windows is in the appendix (p 16).\n\n† RISK11 score threshold at 60% or 26%.\n\n‡ AUC is computed across all score thresholds and value is presented under RISK11 (60).\n\n§ Computed using the prevalence and incidence rates in the trial population as appropriate.\n\n¶ Computed assuming 2% annual incidence of tuberculosis in the population.\n\n‖ NNS for prevalent tuberculosis; NNT for incident tuberculosis. Performance of RISK11 and IGRA for prevalent and incident tuberculosis based on secondary endpoint (≥1 sample+) is in the appendix (p 15).\n\n\n\nThe study was designed to have 90% power to reject the null hypothesis of a RISK11-positive and RISK11-negative cumulative risk ratio less than 2 with one-sided alpha of 0·025. For treatment efficacy there was 80% power to reject the null hypothesis of efficacy less than 20%, with one-sided alpha of 0·05 and under the alternative design hypothesis that efficacy was 80%. To compute statistical power for these aims, a stochastic simulation of the trial was constructed, based on which we expected to observe 33 tuberculosis disease endpoints among 1500 RISK11-positive participants and seven tuberculosis disease endpoints among 1700 RISK11-negative participants (appendix p 6).\n\nRole of the funding source\nThe trial was funded by the Bill & Melinda Gates Foundation (OPP1116632, OPP1137034) and the Strategic Health Innovation Partnerships Unit of the South African Medical Research Council, with funds received from the South African Department of Science and Technology. The Gates Foundation contributed to the study design. The regulatory sponsor was the University of Cape Town. Rifapentine (PRIFTIN) was donated by the manufacturer (Sanofi), who had no role in the design, implementation, analysis, or reporting of the trial. All authors had access to all the data reported in the study. The corresponding author had final responsibility for the decision to submit for publication.\n\nResults\nBetween Sept 20, 2016, and Oct 19, 2018, 20 207 volunteers consented to participation; 16 248 met inclusion criteria at screening and 15 777 with a RISK11 result were potentially eligible for enrolment (figure 2). Of the 20 207 adults assessed for eligibility, common reasons for exclusion included HIV infection (1246 [6·1%]) and comorbid conditions (1369 [6·8%]; appendix p 8). 2923 eligible participants were enrolled after randomisation (1784 [61·0%] RISK11 negative and 1139 [39·0%] RISK11 positive; table 1).Figure 2 Trial profile\n\nITT=intention to treat. mITT=modified intention to treat. LTFU=lost to follow-up. PP=per protocol analysis. *585 participants did not complete the trial for reasons including: 53 (9%) pregnancies, 22 (4%) investigator withdrawals, 46 (8%) consent withdrawals, 26 (4%) HIV infections, 422 (72%) LTFU, and 16 (3%) deaths.\n\n\n\nParticipants were enrolled at five geographically diverse sites across South Africa (appendix pp 9–11). Among participants with a RISK11 result, 1434 (9·3%) of 15 494 were RISK11 positive, with the proportion ranging from 6·2% to 13·0% across the five sites. RISK11-positive participants were randomly asigned either to receive treatment (375 [32·9%] RISK11 positive and 3HP positive) or undergo observation without treatment (764 [67·1%] RISK11 positive and 3HP negative).\n\nThere were no significant differences in smoking history, family history of tuberculosis, or febrile illness between RISK11-positive and RISK11-negative participants (table 1). A higher proportion of RISK11-positive (75 [9·8%] of 364) than RISK11-negative (119 [6·7%] of 1784) participants reported previous tuberculosis disease (p=0·003). Compared with RISK11 negative participants, a greater proportion of RISK11-positive participants were female and mixed race (p<0·001; table 1).\n\nMedian duration of follow-up for incident tuberculosis was 13·9 months (IQR 9·0–15·0) and 1879 (66%) of 2500 3HP-negative mITT participants attended at least six scheduled visits. 1416 (49%) of 2838 participants were followed up for 15 months and 2160 (75%) of 2838 participants were followed up for at least 9 months. 585 (21%) of 2838 participants did not complete the study because of withdrawal, death, or loss to follow-up (figure 2; table 1).\n\nAmong 91 participants with tuberculosis who reached the primary endpoint, 61 were diagnosed with prevalent tuberculosis at baseline (47 RISK11 positive and 14 RISK11 negative; table 1; appendix p 13). Prevalence of tuberculosis in RISK11-positive and RISK11-negative participants was 4·1% (95% CI 3·1–5·4) and 0·78% (0·5–1·3), respectively (figure 3). Thereafter, 24 participants in the untreated group were diagnosed with incident tuberculosis disease (14 RISK11 positive and ten RISK11 negative; table 1; appendix p 13) with overall incidence of 1·05 cases (95% CI 0·59–1·5) per 100 person-years.Figure 3 RISK11 detection of combined prevalent and incident tuberculosis and diagnostic performance\n\n(A) Prevalence of tuberculosis in RISK11-positive (47 cases,) and RISK11-negative (14 cases, red bar) participants at trial enrolment. Error bars depict 95% CI. Cumulative incidence probability of tuberculosis in RISK11-positive (14 cases, blue line) or RISK11-negative (10 cases, red line) mITT participants during follow-up. Shaded areas represent 95% CI. (B) Ratio of RISK11-positive versus RISK11 negative cumulative incidence probability of observing prevalent or incident tuberculosis disease, in the ITT population of the observation group. (C) RISK11 signature scores (each dot represents a participant) measured at screening in trial participants, stratified on tuberculosis diagnosis. Boxes depict IQR, midline represents the median, and whiskers indicate range among enrolled participants. (D) RISK11 signature scores measured at screening in prevalent tuberculosis cases with or without any tuberculosis symptoms, in incident tuberculosis cases or those who did not have a tuberculosis diagnosis. The enrolled population, not the screened population, is represented in (C) and (D), because a large fraction of RISK11-negative participants were not enrolled by design. (E) ROC curves depicting RISK11 diagnostic performance for prevalent tuberculosis in the ITT population, for prevalent tuberculosis among individuals with no symptoms of tuberculosis (asymptomatic) and among individuals with at least one symptom consistent with tuberculosis disease (symptomatic). Shaded areas represent the 95% CI. The grey and black dots indicate the minimum and optimal criteria, respectively, set out in the WHO target product profile for a triage test. The empty dot indicates the criteria set out in the WHO target product profile for a confirmatory diagnostic test. TRP=true positive rate. ITT=intention to treat. FPR=false positive rate. AUC=area under the receiver operating characteristic curve.\n\n\n\nIn the primary analysis of biomarker performance for cumulative tuberculosis, cumulative probability of observing prevalent or incident tuberculosis disease in the ITT population was 0·066 (95% CI 0·049–0·084) in RISK11-positive participants and 0·018 (0·011–0·025) in RISK11-negative participants, with a risk ratio of 3·69 (95% CI 2·25–6·05) over 15 months (figure 3).\n\nA wide range of RISK11 scores was observed, irrespective of tuberculosis outcome (figure 3). Among enrolled participants, those who remained tuberculosis free (controls) had significantly lower RISK11 scores (24·2%, IQR 8·2–75·3) than those with prevalent or incident tuberculosis disease (76·7%, 36·6–94·4; Wilcoxon rank-sum test p<0·0001; figure 3).\n\nIn the secondary analysis of biomarker performance for prevalent tuberculosis, using the prespecified RISK11 test threshold (60%) there was 5·13-times (95% CI 3·01–10·69) increased risk of prevalent tuberculosis disease at baseline in RISK11-positive versus RISK11-negative participants, with sensitivity of 35% (95% CI 24–52) and specificity of 91% (95% CI 91–91; table 2). The receiver operating characteristic (ROC) analysis (figure 3) showed that a RISK11 threshold of 26% provided sensitivity of 72% (95% CI 54–90) and specificity of 75% (95% CI 73–76; table 2); with area under the diagnostic ROC curve (AUC) of 0·77 (95% CI 0·68–0·86). These performance estimates did not meet the minimum criteria for a tuberculosis triage test (table 2). 50 (83·6%) of 61 participants with prevalent tuberculosis had no symptoms compatible with tuberculosis disease, and the remaining 11 participants with at least one symptom consistent with tuberculosis had RISK11 scores of more than 80% (median 96%; figure 3; appendix p 14). Discrimination between symptomatic prevalent tuberculosis and symptomatic controls was high (AUC 0·97, 95% CI 0·95–0·99; figure 3) and, with a highly specific threshold, performance exceeded the optimal TPP for a tuberculosis triage test in this population. By contrast, RISK11 discriminated between asymptomatic controls and asymptomatic prevalent tuberculosis cases with an AUC of 0·75 (95% CI 0·66–0·84; figure 3).\n\nIn the secondary analysis of biomarker performance for incident tuberculosis, annualised incidence was 2·1 versus 0·8 per 100 person-years among the RISK11-positive versus RISK11-negative participants, respectively, which was equivalent to a 0·026 (95% CI 0·01–0·04) versus 0·010 (0·004–0·02) cumulative incident probability of developing tuberculosis disease over 15 months, respectively (figure 3). No incident tuberculosis cases were detected in RISK11-negative participants until 8·7 months (figure 3). Tuberculosis incidence through 15 months among RISK11-positive participants was 2·61 (95% CI 1·15–5·94) times higher than RISK11-negative participants (table 2); and the RISK11 signature discriminated between incident tuberculosis cases and controls with AUC of 0·63 (95% CI 0·47–0·80; figure 4). Over this period, at the predefined 60% threshold, RISK11 showed very low sensitivity of 25% (95% CI 12–46) with specificity of 91% (95% CI 91–91). At an exploratory RISK11 threshold of 26%, which provided 75% specificity, sensitivity was 47% (95% CI 26–74). By comparison, the prognostic sensitivity of IFNγ release assays over 15 months was 83% (62–100), but more than 60% of the population was IFNγ release assay positive (specificity 37%, 95% CI 35–40; table 2).Figure 4 Prognostic performance of RISK11 and treatment efficacy of 3HP\n\n(A) ROC curve depicting RISK11 prognostic performance for incident tuberculosis through 15 months of follow-up. The shaded area represents 95% CI. The grey and black dots depict the minimum and optimal criteria, respectively, set out in the WHO target product profile for an incipient tuberculosis test. (B) RISK11 performance (area under the ROC curve) for endpoints within a 6-month sliding window from month 0 through 15. The shaded area represents 95% CI. (C) ROC curves depicting RISK11 prognostic performance for incident tuberculosis through expanding follow-up periods. The grey and black dots depict the minimum and optimal criteria, respectively, set out in the WHO target product profile for an incipient tuberculosis test. (D) Cumulative incidence of tuberculosis in RISK11-positive participants who were randomly assigned to 3HP (six cases, red line) and RISK11-positive participants who were randomly assigned to observation (14 cases, blue line) during follow-up. The shaded areas represent 95% CI. (E) Cumulative incidence of tuberculosis in participants who met criteria for treatment adherence per protocol, stratified into RISK11-positive participants who were randomly assigned to 3HP (four cases, red line) and RISK11-positive participants who were randomly assigned to observation (14 cases, blue line) during follow-up. (F) TE estimated through follow-up in participants who met criteria for treatment adherence per protocol. The shaded areas represent 95% CI. TRP=true positive rate. FPR=false positive rate. AUC=area under the receiver operating characteristic curve. TPP=target product profile. TE=treatment efficacy.\n\n\n\nRISK11 prognostic performance was highly dependent on time to disease. Instantaneous RISK11 performance, estimated from 6-month sliding windows, showed prognostic discrimination was high (AUC >0·80) for approximately 9 months, before waning towards 0·58 between months 9 and 15 (figure 4; appendix p 16). Prognostic performance of RISK11 for incident tuberculosis within 6 months (AUC 0·95, 95% CI 0·92–1·0) exceeded the optimal TPP for an incipient tuberculosis test (appendix p 16), and for tuberculosis disease within 12 months (0·80, 0·65–0·94; figure 4) approached the minimum TPP (appendix p 16), but over a 15-month period did not meet minimum criteria for a prognostic tuberculosis test (table 2).\n\nIn the primary analysis of treatment efficacy among RISK11-positive participants, tuberculosis incidence in the 3HP-positive and 3HP-negative groups was 1·94 cases per 100 person years and 2·09 cases per 100 person years, respectively (figure 4; table 1), with estimated treatment efficacy of 7·0% (95% CI −145 to 64·7) over 15 months. In the subgroup of 286 adherent participants who completed at least 11 doses within 16 weeks, efficacy was 22% (−138 to 74; figure 4) over 15 months. Notably, among adherent participants, there were no tuberculosis cases through 9 months (figure 4).\n\nAdverse events related to 3HP were mostly of mild to moderate severity (appendix p 12). 67 serious adverse events, including 29 due to trauma, occurred in 65 participants. Serious adverse events occurred in 20 (5·3%) of 375 RISK11-positive participants who received 3HP (eight serious adverse events due to trauma), compared with 12 (1·6%) of 764 in RISK11-positive and 3HP-negative participants (Fisher's exact p<0·001). Among RISK11-negative participants, 33 (1·9%) of 1784 experienced serious adverse events. All but two serious adverse events were deemed unrelated to 3HP. Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). One death of unknown cause also occurred in an untreated RISK11-negative participant. There were 16 deaths in total, including five RISK11-positive participants receiving 3HP (three deaths due to trauma), three untreated RISK11-positive participants, and eight RISK11-negative participants.\n\n3HP was halted in 28 (7·5%) of 375 participants, due to an adverse event of special interest (influenza-like illness or other possible hypersensitivity reaction) in 17 (4·5%), hepatotoxicity in one (0·3%), gastrointestinal symptoms in three (0·8%), and seizures in three (0·8%) participants.\n\nRISK11 diagnostic and prognostic performance and treatment efficacy of 3HP based on the secondary endpoint definition (at least one sputum sample; appendix p 14) are described in the appendix (p 15).\n\nFive (8·2%) of the 61 participants witih prevalent tuberculosis were resistant to isoniazid or rifampicin, or both. Two (6·7%) of the 30 participants with incident tuberculosis, both in the untreated group, were resistant to isoniazid and rifampicin. No participants were observed to have drug-resistant incident tuberculosis in the 3HP-positive group.\n\nDiscussion\nOur goal was to evaluate a biomarker-targeted, community-based strategy to detect missing tuberculosis cases among people who do not seek health care, whose disease might not be detected by symptom-focused screening algorithms, and to prevent disease among those at highest risk of progression to tuberculosis. The RISK11 assay was an effective screening test for active disease in symptomatic participants, in whom performance exceeded the requirements for a triage test, but less so in asymptomatic participants. The RISK11 signature was able to predict risk for tuberculosis disease progression, in a trial population with tuberculosis incidence exceeding one case per 100 person-years, but optimal prognostic performance was limited to a 6-month horizon. While risk-targeted 3HP did not prevent tuberculosis disease over 15 months, there was some evidence of transient efficacy through 9 months among fully adherent participants.\n\nCommunity-based recruitment of ambulant volunteers was not focused on individuals with known risk factors for tuberculosis, such as household contact. Individuals with recent previous history of tuberculosis (>3 years before screening) and HIV infection were excluded. Nevertheless, more than 1% of study volunteers had previously undiagnosed, microbiologically confirmed tuberculosis at enrolment, based on spontaneous expectorated rather than induced sputum samples. More than 80% of these baseline tuberculosis cases did not have any symptom compatible with tuberculosis disease and would not have been detected by a tuberculosis screening strategy that requires symptoms as the entry point to investigation. This finding is consistent with 46–79% prevalence (median 50%) of subclinical tuberculosis reported in prevalence surveys.12, 13, 14 It is not known whether subclinical tuberculosis would have progressed to symptomatic disease, spontaneously halted, or even reversed if left untreated,15, 16 nor whether subclinical disease directly contributes to M tuberculosis transmission.17 Further research is needed to determine the importance of detection, treatment, and prevention of subclinical disease for global tuberculosis control.\n\nAlthough very few prevalent tuberculosis cases were symptomatic, RISK11 performance for discrimination of symptomatic prevalent tuberculosis cases from symptomatic controls exceeded the optimal TPP criteria for a triage test, while not meeting the stringent criteria for a confirmatory diagnostic test.5 A 2020 prospective observational study among symptomatic individuals who self-presented to a tuberculosis clinic assessed diagnostic accuracy of 27 transcriptomic signatures for discrimination between prevalent tuberculosis cases and controls.18 The 16-gene Zak signature, from which RISK11 was derived, did not meet the minimum WHO criteria for a triage test, but four of the 27 signatures met these criteria, suggesting that another signature might perform as well as or better than RISK11. RISK11 discrimination of asymptomatic prevalent tuberculosis cases from asymptomatic controls was modest and did not meet the minimal criteria for a triage test. These findings suggest that host blood biomarker development must consider that subclinical tuberculosis might be characterised by more heterogenous or less pronounced peripheral blood inflammatory responses than symptomatic tuberculosis, or both, which affects RNA signature performance. This finding is consistent with lower inflammatory profiles, observed by blood transcriptomic and proteomic analyses, during the subclinical phases of tuberculosis progression compared with subsequent symptomatic, active disease.19, 20 The modest performance characteristics for asymptomatic prevalent tuberculosis would limit applicability of RISK11 for biomarker-targeted, mass community screening in the South African setting, where the majority of baseline tuberculosis cases were subclinical. A host blood biomarker with good sensitivity and specificity for symptomatic tuberculosis might be most useful in countries with low to medium tuberculosis burden, where individuals with compatible symptoms might not otherwise be investigated for tuberculosis. Future diagnostic studies in symptomatic patients seeking health care should also include patients with extrapulmonary and culture-negative tuberculosis, particularly in HIV-infected cohorts, and the full spectrum of differential diagnoses that commonly mimic tuberculosis.\n\nPrognostic performance of RISK11 for risk of progression to incident tuberculosis was poor through 15 months and did not meet the minimum TPP criteria for an incipient tuberculosis test through this prognostic horizon.4 However, good prognostic performance was observed for incident tuberculosis within 12 months of testing and performance exceeded the optimal TPP criteria for tuberculosis occurring within 6 months of testing. The positive predictive value for incident disease (1·9 vs 0·9 for RISK11 compared with IFNγ release assay, respectively) was computed from the observed tuberculosis incidence rate, which was lower than that typically used in estimations (2%).3, 6 It is not possible to determine whether the late incident tuberculosis cases occurring among RISK11-negative participants were due to reactivation or new M tuberculosis infection. We infer that a prognostic test with optimal short-term performance might be useful in identifying people who would benefit from an efficacious intervention in a low-incidence setting, in which the timing of M tuberculosis exposure is often known and subsequent exposure is unlikely.\n\nThe 3HP regimen was previously shown to be as effective as 9 months of isoniazid in preventing tuberculosis among individuals with known exposure or positive TST.21 Ethical equipoise of the intervention and control groups in this trial was based on the fact that RISK11 had been validated in selected case-control studies, which can overestimate biomarker performance, and thus risk for tuberculosis among RISK11-positive individuals needed to be tested prospectively in the field. Furthermore, although TPT is given commonly to IFNγ release assay-positive and tuberculin skin test-positive individuals, and individuals with known household exposure to a tuberculosis patient, the vast majority do not progress to tuberculosis disease if left untreated. The risk–benefit balance of 3HP preventive therapy for RISK11-positive individuals was unknown. However, we found no evidence that 3HP treatment reduced the rate of incident tuberculosis over 15 months in RISK11-positive individuals, who might be further advanced along the spectrum of tuberculosis pathogenesis.19 Interpretation of the results is limited by the wide CIs. It is also notable that no tuberculosis cases were observed in fully adherent participants through 9 months. This finding is consistent with the possibility that 3HP was sufficient to temporarily halt, but insufficient to sterilise, incipient tuberculosis, resulting in reactivation. A RISK11-targeted preventive therapy strategy for high tuberculosis transmission settings like South Africa might require a more potent therapeutic regimen than 3HP. 3HP might have been sufficient to sterilise incipient tuberculosis disease, but not to protect against tuberculosis disease resulting from reinfection after completion of the treatment course. Although it is not possible to distinguish between reactivation and reinfection tuberculosis cases in this study, we suggest that the limited time available for reinfection and subsequent progression to disease after completing 3HP makes the latter possibility less likely.\n\nThe study was subject to a number of limitations. The hybrid design required an open-label treatment group,2 with no placebo for RISK11-positive participants, so that risk for tuberculosis could also be evaluated in the control group while concealing RISK11 status from participants, site staff, and tuberculosis endpoint laboratory staff for analysis of biomarker performance. Tuberculosis case accrual during the latter stages of follow-up suggested no evidence of ascertainment bias during treatment. Extensive study simulations were done to inform the size of each group for the coprimary analyses. However, due to lower than expected prevalence of RISK11-positive status in the screened population (9·3% vs 15%), enrolment of 1139 RISK11-positive individuals required 2 years, compared with planned enrolment of 1500 RISK11-positive individuals over 1 year. As a result, fewer than expected incident tuberculosis outcomes were observed (24 vs 40 primary endpoints), which might have reduced power for both treatment efficacy and RISK11 performance analyses. Not all participants in the treatment group completed 3HP per protocol, because study drug was discontinued for suspected hypersensitivity reactions or influenza-like illnesses. However, the discontinuation rate (7·5%) was comparable to other trials of 3HP, in which study drug was discontinued in 17·9% of participants overall and in 4·9% due to an adverse event.21 The loss to follow-up rate in this trial (14·4%) was higher than expected and might reflect the challenges of retaining the study participants, in the absence of traditional tuberculosis risk factors for which surveillance is routine. However, loss to follow-up occurred predominantly after the treatment period and did not seem to have been biased by treatment factors. We note that median duration of participation was 13·9 months and thus loss to follow-up did not have major unforeseen effect on statistical power. Strengths of the study include enrolment in geographically distinct sites across South Africa that were representative of populations with different rates of IFNγ release assay positivity and tuberculosis disease, which were congruent with local rates of RISK11 positivity, although the sample size was not sufficient for analysis of signature performance or 3HP efficacy at site level. The findings broadly reflect the South African tuberculosis epidemic, but might not be directly applicable to countries with much lower tuberculosis incidence.\n\nIt is not yet known whether other parsimonious tuberculosis signatures, developed and validated like RISK11 in carefully curated case-control studies, will exhibit similar performance characteristics when prospectively tested in the field, where undiagnosed subclinical tuberculosis might pose a challenge to diagnostic performance. Head-to-head analyses of several transcriptomic tuberculosis signatures with promising diagnostic performance are currently underway on CORTIS samples and novel near-patient testing platforms are in development, which might bring cost-effective, community-based tuberculosis biomarker screening closer to implementation in the field. However, although we have shown that a strategy of biomarker-guided tuberculosis preventive therapy is feasible, the optimal preventive therapy regimen for use in such a strategy remains elusive.\n\nData sharing\nDeidentified RISK11 signature scores and primary tuberculosis endpoint data from all participants will be available with publication. The dataset is deposited in Zivahub (https://doi.org/10.25375/uct.13573337.v1), an open access data repository hosted by the University of Cape Town's institutional data repository powered by Figshare for Institutions.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nThe trial was funded by the Bill & Melinda Gates Foundation (OPP1116632, OPP1137034) and the Strategic Health Innovation Partnerships Unit of the South African Medical Research Council with funds received from the South African Department of Science and Technology. Rifapentine was donated by the manufacturer (Sanofi). The authors thank the members of the data and safety monitoring board and the trial steering committee.\n\nContributors\nTJS, AF-G, AP-N, SS, GW, KN, GC, and MH designed the study. CI, WB, AH, STM, RH-M, MT, GW, KN, and GC recruited and evaluated participants. TJS, AP-N, SKM, SCM, KH, MM, NB, ME, LJ, and RR collected and analysed laboratory data. AF-G, and BB accessed and verified the data. TJS, AF-G, AP-N, HM, BB, TS, RGW, and MH analysed data and interpreted results. KH, CH, and MK provided operational support. TJS, AF-G, HM, and MH drafted the Article. All authors had full access to the data, and reviewed, revised and gave final approval of the Article before submission.\n\nThe CORTIS-01 Study Team\nKesenogile Baepanye, Tshepiso Baepanye, Ken Clarke, Marelize Collignon, Audrey Dlamini, Candice Eyre, Tebogo Feni, Moogo Fikizolo, Phinda Galane, Thelma Goliath, Alia Gangat, Shirley Malefo-Grootboom, Elba Janse van Rensburg, Bonita Janse van Rensburg, Sophy Kekana, Marietjie Zietsman, Adrianne Kock, Israel Kunene, Aneessa Lakhi, Nondumiso Langa, Hilda Ledwaba, Marillyn Luphoko, Immaculate Mabasa, Dorah Mabe, Nkosinathi Mabuza, Molly Majola, Mantai Makhetha, Mpho Makoanyane, Blossom Makhubalo, Vernon Malay, Juanita Market, Selvy Matshego, Nontsikelelo Mbipa, Tsiamo Mmotsa, Sylvester Modipa, Samuel Mopati, Palesa Moswegu, Primrose Mothaga, Dorothy Muller, Grace Nchwe, Maryna Nel, Lindiwe Nhlangulela, Bantubonke Ntamo, Lawerence Ntoahae, Tedrius Ntshauba, Nomsa Sanyaka, Letlhogonolo Seabela, Pearl Selepe, Melissa Senne, MG Serake, Maria Thlapi, Vincent Tshikovhi, Lebogang Tswaile, Amanda van Aswegen, Lungile Mbata, Constance Takavamanya, Pedro Pinho, John Mdlulu, Marthinette Taljaard, Naydene Slabbert, Sharfuddin Sayed, Tanya Nielson, Melissa Senne, Ni Ni Sein, Lungile Mbata (The Aurum Institute); Dhineshree Govender, Tilagavathy Chinappa, Mbali Ignatia Zulu, Nonhle Bridgette Maphanga, Senzo Ralph Hlathi, Goodness Khanyisile Gumede, Thandiwe Yvonne Shezi, Jabulisiwe Lethabo Maphanga, Zandile Patrica Jali, Thobelani Cwele, Nonhlanhla Zanele Elsie Gwamanda, Celaphiwe Dlamini, Zibuyile Phindile Penlee Sing, Ntombozuko Gloria Ntanjana, Sphelele Simo Nzimande, Siyabonga Mbatha, Bhavna Maharaj, Atika Moosa, Cara-Mia Corris (Centre for the AIDS Programme of Research in South Africa); Fazlin Kafaar, Marwou De Kock, Hennie Geldenhuys, Angelique Kany Kany Luabeya, Justin Shenje, Natasja Botes, Susan Rossouw, Hadn Africa, Bongani Diamond, Samentra Braaf, Sonia Stryers, Alida Carstens, Ruwiyda Jansen, Simbarashe Mabwe, Roxane Herling, Ashley Veldsman, Lebohgang Makhete, Marcia Steyn, Sivuyile Buhlungu, Margareth Erasmus, Ilse Davids, Patiswa Plaatjie, Alessandro Companie, Frances Ratangee, Helen Veldtsman, Christel Petersen, Charmaine Abrahams, Miriam Moses, Xoliswa Kelepu, Yolande Gregg, Liticia Swanepoel, Nomsitho Magawu, Nompumelelo Cetywayo, Lauren Mactavie, Habibullah Valley, Elizabeth Filander, Nambitha Nqakala, Angelique Mouton, Fajwa Opperman, Elma Van Rooyen, Petrus Tyambetyu (South African Tuberculosis Vaccine Initiative, University of Cape Town); Elizna Maasdorp, Justine Khoury, Belinda Kriel, Bronwyn Smith, Liesel Muller, Susanne Tonsing, Andre Loxton, Andriette Hiemstra, Petri Ahlers, Marika Flinn (DST/NRF Centre of Excellence for Biomedical TB Research and SAMRC Centre for TB Research, Stellenbosch University); and Eva Chung, Michelle Chung, Alicia Sato (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center)\n\nDeclaration of interests\nTJS has a patent of the RISK11 signature pending and reports grants from the Bill and Melinda Gates Foundation and South African Medical Research Council. KN reports grants from CAPRISA. GW reports a patent (PCT/IB2019/052043) pending to University of Cape Town, Stellenbosch University, Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften EV, Seattle Children's Hospital Doing Business as Seattle Children's Research Institute, and UK Research and Innovation. GC reports grants from the Bill & Melinda Gates Foundation. AP-N has a patent of the RISK11 signature pending and reports grants from the Bill & Melinda Gates Foundation and the South African Medical Research Council. MH reports grants from the Bill & Melinda Gates Foundation and the South African Medical Research Council.\n==== Refs\nReferences\n1 Behr MA Edelstein PH Ramakrishnan L Is Mycobacterium tuberculosis infection life long? BMJ 367 2019 l5770 \n2 Fiore-Gartland A Carpp LN Naidoo K Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention Tuberculosis 109 2018 61 68 29559122 \n3 Petruccioli E Scriba TJ Petrone L Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis Eur Respir J 48 2016 1751 1763 27836953 \n4 Sumner T Scriba TJ Penn-Nicholson A Hatherill M White RG Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy Sci Rep 9 2019 11126 11130 31366947 \n5 WHO High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting 2014 World Health Organization Geneva https://apps.who.int/iris/bitstream/handle/10665/135617/WHO_HTM_TB_2014.18_eng.pdf \n6 WHO FIND Development of a Target Product Profile (TPP) and a framework for evaluation for a test for predicting progression from tuberculosis infection to active disease 2017 World Health Organization Geneva https://apps.who.int/iris/bitstream/handle/10665/259176/WHO-HTM-TB-2017.18-eng.pdf \n7 Penn-Nicholson A Scriba TJ Hatherill M White RG Sumner T A novel blood test for tuberculosis prevention and treatment S Afr Med J 107 2016 4 5 28112082 \n8 Zak DE Penn-Nicholson A Scriba TJ A blood RNA signature for tuberculosis disease risk: a prospective cohort study Lancet 387 2016 2312 2322 27017310 \n9 Darboe F Mbandi SK Naidoo K Detection of tuberculosis recurrence, diagnosis and treatment response by a blood transcriptomic risk signature in HIV-infected persons on antiretroviral therapy Front Microbiol 10 2019 1441 \n10 Darboe F Mbandi SK Thompson EG Diagnostic performance of an optimized transcriptomic signature of risk of tuberculosis in cryopreserved peripheral blood mononuclear cells Tuberculosis 108 2018 124 126 29523312 \n11 Gupta RK Turner CT Venturini C Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis Lancet Respir Med 8 2020 395 406 31958400 \n12 Onozaki I Law I Sismanidis C Zignol M Glaziou P Floyd K National tuberculosis prevalence surveys in Asia, 1990–2012: an overview of results and lessons learned Trop Med Int Health 20 2015 1128 1145 25943163 \n13 Gunasekera K Cohen T Gao W Ayles H Godfrey-Faussett P Claassens M Smoking and HIV associated with subclinical tuberculosis: analysis of a population-based prevalence survey Int J Tuberc Lung Dis 24 2020 340 346 32228765 \n14 Frascella B Richards AS Sossen B Subclinical tuberculosis disease—a review and analysis of prevalence surveys to inform definitions, burden, associations and screening methodology Clin Infect Dis 2020 published online Sept 16. 10.1093/cid/ciaa1402 \n15 Drain PK Bajema KL Dowdy D Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection Clin Microbiol Rev 31 2018 e00021 e00028 \n16 Tiemersma EW van der Werf MJ Borgdorff MW Williams BG Nagelkerke NJ Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review PLoS One 6 2011 e17601 \n17 Dowdy DW Basu S Andrews JR Is passive diagnosis enough? The impact of subclinical disease on diagnostic strategies for tuberculosis Am J Respir Crit Care Med 187 2013 543 551 23262515 \n18 Turner CT Gupta RK Tsaliki E Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study Lancet Respir Med 8 2020 407 419 32178775 \n19 Scriba TJ Penn-Nicholson A Shankar S Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease PLoS Pathog 13 2017 e1006687 \n20 Moreira-Teixeira L Tabone O Graham CM Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis Nat Immunol 21 2020 464 476 32205882 \n21 Sterling TR Villarino ME Borisov AS Three months of rifapentine and isoniazid for latent tuberculosis infection N Engl J Med 365 2011 2155 2166 22150035\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1473-3099",
"issue": "21(3)",
"journal": "The Lancet. Infectious diseases",
"keywords": null,
"medline_ta": "Lancet Infect Dis",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D015415:Biomarkers; D004334:Drug Administration Schedule; D005260:Female; D018023:HIV Seronegativity; D006801:Humans; D015994:Incidence; D007538:Isoniazid; D008297:Male; D009169:Mycobacterium tuberculosis; D012329:RNA, Bacterial; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin; D013019:South Africa; D016896:Treatment Outcome; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "101130150",
"other_id": null,
"pages": "354-365",
"pmc": null,
"pmid": "33508224",
"pubdate": "2021-03",
"publication_types": "D017427:Clinical Trial, Phase II; D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "29523312;32178775;31649096;32228765;21483732;22150035;31297103;28112082;29559122;31958400;25943163;29145483;32936877;27836953;30021818;23262515;31366947;32205882;27017310",
"title": "Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial.",
"title_normalized": "biomarker guided tuberculosis preventive therapy cortis a randomised controlled trial"
} | [
{
"companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2021-00646",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "This report presents a case of Bloom syndrome (BS) in a consanguineous Saudi family. The patient, an 11-year-old male with mature B-cell lymphoma, had minimal therapeutic response and significant dose-limiting toxicity with standard chemotherapy treatment. He later responded successfully to a rituximab-based chemotherapy protocol. This case highlights that the rituximab-based chemotherapy protocol is an effective and safe treatment alternative for mature B-cell lymphoma in patients with BS. Further trials are warranted to investigate this modality of treatment.",
"affiliations": "College of Medicine, Department of Pediatrics, Umm AlQura University, Makkah, Saudi Arabia.",
"authors": "Jastaniah|Wasil|W|",
"chemical_list": "D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(7)",
"journal": "Pediatric blood & cancer",
"keywords": "B-cell lymphoma; Bloom syndrome; chemotherapy; rituximab",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001816:Bloom Syndrome; D002648:Child; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27966805",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a patient with Bloom syndrome.",
"title_normalized": "successful treatment of mature b cell lymphoma with rituximab based chemotherapy in a patient with bloom syndrome"
} | [
{
"companynumb": "SA-ALVOGEN-2017-ALVOGEN-092416",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "To identify clinical and environmental factors associated with an outbreak of hospital-onset, healthcare facility-associated Clostridium difficile infection (HO-HCFA CDI).\n\n\n\nCase-control study.\n\n\n\nPublic, acute care, academic tertiary referral center in Mexico.\n\n\n\nAdults hospitalized ≥48 hours between January 2015 and December 2016 were included. Cases were patients with a first episode of HO-HCFA CDI. Controls were patients with any other diagnosis; they were randomly selected from the hospital discharge database and matched in a 1:2 manner according to the date of diagnosis of case ± 10 days. Variables with p<0.1 were considered for multivariable analysis.\n\n\n\nOne hundred and fifty-five cases and 310 controls were included. Variables independently associated with HO-HCFA CDI were: exposure to both ciprofloxacin and proton pump inhibitor (PPI) within the last 3 months (OR = 8.07, 95% CI = 1.70-38.16), febrile neutropenia (OR = 4.61, 95% CI = 1.37-15.46), intraabdominal infection (OR = 2.06, 95% CI = 0.95-4.46), referral from other hospitals (OR = 1.99, 95% CI = 0.98-4.05) and an increasing number of antibiotics previously used (OR = 1.28, 95% CI = 1.13-1.46).\n\n\n\nMultiple factors were found to be associated with the first episode of HO-HCFA CDI in the setting of an outbreak; of the modifiable risk factors, prior exposure to both ciprofloxacin and PPI was the most important. Referral from other hospitals was an environmental risk factor that deserves further study.",
"affiliations": "Department of Hospital Epidemiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Microbiology Laboratory, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Microbiology Laboratory, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Epidemiology and Health Services Research Unit, Aging Area, Instituto Mexicano del Seguro Social, Mexico City, Mexico.;Department of Hospital Epidemiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.",
"authors": "Ochoa-Hein|Eric|E|;Sifuentes-Osornio|José|J|;Ponce de León-Garduño|Alfredo|A|;Torres-González|Pedro|P|;Granados-García|Víctor|V|;Galindo-Fraga|Arturo|A|0000-0002-2818-1160",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0198212",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0198212PONE-D-17-40502Research ArticleMedicine and Health SciencesPharmacologyDrugsAntimicrobialsAntibioticsBiology and Life SciencesMicrobiologyMicrobial ControlAntimicrobialsAntibioticsMedicine and Health SciencesHealth CareHealth Care FacilitiesHospitalsBiology and Life SciencesOrganismsBacteriaGut BacteriaClostridium DifficileMedicine and Health SciencesEpidemiologyMedicine and Health SciencesPublic and Occupational HealthHygieneMedicine and Health SciencesHealth CareHealth Care FacilitiesBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsNeutropeniaBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsNeutropeniaBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaComputer and Information SciencesData VisualizationInfographicsChartsFactors associated with an outbreak of hospital-onset, healthcare facility-associated Clostridium difficile infection (HO-HCFA CDI) in a Mexican tertiary care hospital: A case-control study Clostridium difficile outbreak in Mexican hospitalOchoa-Hein Eric ConceptualizationFormal analysisInvestigationMethodologyProject administrationSupervisionWriting – original draft1Sifuentes-Osornio José ConceptualizationFormal analysisMethodologyProject administrationResourcesSupervisionVisualizationWriting – review & editing2Ponce de León-Garduño Alfredo Formal analysisResourcesSupervisionVisualizationWriting – review & editing3Torres-González Pedro Formal analysisResourcesSupervisionVisualizationWriting – review & editing3Granados-García Víctor ConceptualizationFormal analysisMethodologyProject administrationResourcesSupervisionVisualizationWriting – review & editing4http://orcid.org/0000-0002-2818-1160Galindo-Fraga Arturo ConceptualizationFormal analysisMethodologyProject administrationResourcesSupervisionVisualizationWriting – review & editing1*1 \nDepartment of Hospital Epidemiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico2 \nDepartment of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico3 \nMicrobiology Laboratory, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico4 \nEpidemiology and Health Services Research Unit, Aging Area, Instituto Mexicano del Seguro Social, Mexico City, MexicoDeshpande Abhishek EditorCleveland Clinic, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: arturo.galindof@incmnsz.mx29 5 2018 2018 13 5 e019821215 11 2017 15 5 2018 © 2018 Ochoa-Hein et al2018Ochoa-Hein et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nTo identify clinical and environmental factors associated with an outbreak of hospital-onset, healthcare facility-associated Clostridium difficile infection (HO-HCFA CDI).\n\nDesign\nCase-control study.\n\nSetting\nPublic, acute care, academic tertiary referral center in Mexico.\n\nPatients\nAdults hospitalized ≥48 hours between January 2015 and December 2016 were included. Cases were patients with a first episode of HO-HCFA CDI. Controls were patients with any other diagnosis; they were randomly selected from the hospital discharge database and matched in a 1:2 manner according to the date of diagnosis of case ± 10 days. Variables with p<0.1 were considered for multivariable analysis.\n\nResults\nOne hundred and fifty-five cases and 310 controls were included. Variables independently associated with HO-HCFA CDI were: exposure to both ciprofloxacin and proton pump inhibitor (PPI) within the last 3 months (OR = 8.07, 95% CI = 1.70–38.16), febrile neutropenia (OR = 4.61, 95% CI = 1.37–15.46), intraabdominal infection (OR = 2.06, 95% CI = 0.95–4.46), referral from other hospitals (OR = 1.99, 95% CI = 0.98–4.05) and an increasing number of antibiotics previously used (OR = 1.28, 95% CI = 1.13–1.46).\n\nConclusions\nMultiple factors were found to be associated with the first episode of HO-HCFA CDI in the setting of an outbreak; of the modifiable risk factors, prior exposure to both ciprofloxacin and PPI was the most important. Referral from other hospitals was an environmental risk factor that deserves further study.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nThe burden imposed by Clostridium difficile infection (CDI) on hospitals and communities is dangerously increasing worldwide [1]. CDI is the most frequent healthcare-associated infection and the main cause of gastroenteritis-associated death in the United States (107,600 hospital-onset infections and 29,000 related deaths in 2011, respectively) [1, 2]. Direct costs related to acute hospital care due to CDI are substantial ($4.8 billion in the United States in 2008) [1].\n\nAlthough some risk factors for CDI are well established, some differences between study populations have been noted. For instance, although advanced age has been cited as one of the most consistent risk factors for CDI in developed nations, this may not be the case in Latin American countries [3–6]. In our hospital, carbapenems, piperacillin/tazobactam, ceftriaxone and vancomycin are frequently prescribed and are suspected to have a role in CDI risk, despite the fact that clindamycin and quinolones have been the main antibiotics historically associated with CDI. Finally, some reports have shown that the environment plays an important role as a risk factor [7–12], but this has not been confirmed in all settings.\n\nAt the beginning of 2015, an outbreak of hospital-onset, healthcare facility-associated CDI (HO-HCFA CDI) was declared in our hospital and it has continued ever since. Therefore, the aim of this study was to identify the clinical and environmental factors associated with HO-HCFA CDI cases in the setting of an outbreak in a tertiary referral hospital in Mexico City.\n\nMethods\nWe conducted a case-control study in a public, acute care, academic tertiary care referral hospital. Adult patients hospitalized ≥48 hours in General Wards (167 beds), the Emergency Room (28 beds), the Intensive Care Unit (14 beds), and the Short-Stay Surgery Ward (12 beds) between January 2015 and December 2016 were included; those hospitalized in the Outpatient Parenteral Antimicrobial Therapy rooms and the Postoperative Recovery rooms were not included (9 beds in total). The study was approved by the Institutional Review Board (REF. 1845) and informed consent was waived due to the retrospective nature of the analysis.\n\nCases were patients who had a first episode of HO-HCFA CDI, which was defined according to the 2010 guidelines [13]: at least three episodes of Bristol chart [14] type 6 or 7 unformed stools in a 24-hour period, acquired after 48 hours of hospitalization and up to hospital discharge. We confirmed the diagnosis by using a two-step algorithm consisting of a positive glutamate-dehydrogenase assay (VIDAS®\nC. difficile GDH, Biomérieux, Marcy-l’Étoile, France) followed by a positive A & B toxin-gene amplification test (GeneXpert®\nC. difficile/Epi test, Cepheid, Sunnyvale, California, United States). This testing algorithm has been in use in the hospital since 2013 (in previous years, the GDH assay had been followed by the VIDAS® CD A&B toxin detection kit) [15]. All cases were diagnosed by the treating physicians and were registered by the Department of Hospital Epidemiology, according to routine active epidemiological surveillance policies. Patients with a recurrent, indeterminate, community-associated or community-onset, healthcare facility-associated CDI episode as defined by the 2010 guidelines [13] were excluded. Although recurrent CDI cases are one of the most important risk factors for CDI, we decided to exclude them, as we were particularly interested in defining risk factors for a first episode of HO-HCFA CDI in our setting.\n\nControls were patients with any discharge diagnosis, except ICD-10 code A04.7 (enterocolitis due to C. difficile). During the study period, the 2014, 2015 and 2016 versions of ICD-10 were used; updating of ICD-10 versions did not affect the case definition that relied on the A04.7 code [16]. All patients with onset of diarrhea in our hospital undergo testing for CDI due to a high prevalence of risk factors for CDI; therefore, those with diarrhea and a negative workup for CDI were also included. Both the medical records and the Hospital Epidemiology database were checked to further verify the absence of any episode of CDI among controls as far back as 3 months before inclusion into the study. Controls were randomly selected from the hospital discharge database with the aid of a simple random number sequence generated in the internet link https://www.randomizer.org. Two controls were matched to each case according to the date of diagnosis of the case ±10 days (which is an arbitrary time period that tried to take into account unknown risk factors possibly related to hospitalization).\n\nCases and controls whose medical charts were unavailable for consultation were eliminated, but in order to keep the 1:2 matching we used the selection criteria previously defined to replace the eliminated controls with others.\n\nAccording to information in the Hospital Epidemiology database, it was expected that a room previously occupied by a case would be the factor with the least prevalence in the study population (approximately 19%); therefore, a sample including all cases (n = 161) was deemed to be sufficiently powered to detect an odds ratio of at least 1.92 for the presumed associated factors, assuming a type I error rate of 5%.\n\nThe following variables were collected from medical charts: sex, age, economic status, comorbidities, Charlson comorbidity index, date of diagnosis of cases, C. difficile ribotype for cases (027 or non-027), hospital admission and discharge dates, length of stay (overall length of stay for cases and controls, and length of stay before diagnosis of CDI for cases), and vital status at discharge and at 30 days after discharge. Use of at least one dose of a systemic drug (antibiotics, proton pump inhibitors [PPI], corticosteroids, immunosuppressants and antineoplastic drugs), gastrointestinal surgery, previous hospitalizations, referral from another hospital, and hospitalization in rooms previously occupied by cases were evaluated as far back as 3 months before the date of diagnosis of CDI (cases) or date of hospital discharge (controls). Additionally, rooms occupied by cases and controls during the hospital stay up until the date of diagnosis of CDI (cases) or date of hospital discharge (controls) were registered. We consulted the Hospital Epidemiology database to determine the use of hydrogen peroxide vapor for terminal room disinfection within the last 2 weeks before admission of a case or control to the last occupied bed. Clostridium difficile-associated disease pressure values (henceforth referred to as CDI pressure values) were calculated for cases and controls according to previously published methods [17].\n\nIn addition to the analysis of the environmental variables previously mentioned, and in an attempt to determine if cross-transmission may have happened, the rooms occupied by cases at the moment of diagnosis, as well as the infecting ribotype (027 or non-027), were visually analyzed by means of a slideshow, which is shown in S1 File.\n\nThe following hospital-wide preventive strategies were strengthened upon outbreak detection: a) antibiotic stewardship measures, consisting of automatic alerts, prior authorization and prospective audit and feedback; b) terminal room disinfection with 5,000 ppm of sodium hypochlorite or hydrogen peroxide vapor in rooms occupied by CDI cases (otherwise, 1,000 ppm of sodium hypochlorite was used); c) promotion of hand hygiene in all hospital areas with special emphasis on use of 2% chlorhexidine soap and water after contact with cases; d) strict use of contact precautions on any patient with diarrhea; e) use of 0.5% activated hydrogen peroxide wipes for disinfection of medical instruments in the cohort area (defined below); and f) assignment and disinfection of metal commodes for repeated use by patients in the cohort area.\n\nAdherence to the preventive strategies was only routinely measured for hand hygiene (with either soap and water or alcohol hand rub). This was determined by direct observation of personnel before and after contact with patients, as done routinely during active epidemiological surveillance.\n\nCohorting of patients with confirmed CDI in the designated area of the second floor was started in March 2015 (see S1 File). This was intended to facilitate adherence to hand hygiene with soap and water due to better availability of sinks and to reduce the influx of visitors and personnel because this area is located at one of the two dead ends of the second floor.\n\nSeparately, hospital-wide broad-spectrum antibiotic consumption from 2012 to 2016 was measured using defined daily doses (DDD), according to WHO standards [18]. Briefly, the Pharmacy Department provided the annual number of vials used for each antibiotic: the total annual amount of each antibiotic was first converted to total annual grams and then to annual DDD; the latter was then standardized to 1,000 patient-days for each year. Quinolones (ciprofloxacin and moxifloxacin), clindamycin, carbapenems (ertapenem, imipenem and meropenem), piperacillin/tazobactam, vancomycin and ceftriaxone were included in this analysis.\n\nStatistical analysis was performed with Stata version 14.0 (StataCorp, College Station, TX, USA). Missing values could not be replaced. Absolute and relative frequencies were used to describe categorical variables, and medians and interquartile ranges (IQR) were used to describe non-normally distributed variables. Bivariate analysis of categorical variables was performed with either chi-square test or Fisher’s exact test, as appropriate; two-sample Wilcoxon Rank sum test was used for ordinal and numerical variables. Odds ratios (OR) with their respective 95% confidence intervals (95% CI) and statistical significance were calculated. Variables with p values ≤0.1 were included in multivariable analysis and retained in the model if the p value remained ≤0.1, as has been suggested by another group of authors [19]. Interaction and confounding were intentionally investigated and only statistically significant findings are reported in this paper (interaction terms and interaction analysis can be further consulted in S2 and S3 Files).\n\nResults\nDuring the study period, a median rate of 11.5 cases of HO-HCFA CDI per 10,000 patient-days per month was observed (IQR = 7.4–15.3), as compared with a median rate of 7.0 cases per 10,000 patient-days in 2014 (IQR = 5.4–8.0), p = 0.002 (Fig 1). The mean hand hygiene adherence rate across the study period was 43.8±10.4% (Fig 1).\n\n10.1371/journal.pone.0198212.g001Fig 1 HO-HCFA CDI monthly rates per 10,000 patient-days and hand hygiene monthly adherence rates.\nContinuous line: C. difficile infection rates; dashed line: hand hygiene adherence rates (with either soap and water or alcohol hand rub).\n\nA total of 329 CDI cases were confirmed during the study period. Forty-eight recurrent cases (14.6%), 13 indeterminate cases (3.9%), 37 community-associated cases (11.2%), and 70 community-onset, healthcare facility-associated cases (21.3%) were excluded; after elimination of 6 HO-HCFA CDI cases due to unavailable medical charts, a total of 155 cases were included for analysis. Of 310 controls selected, 14 were eliminated due to unavailable medical charts and were randomly replaced with others.\n\nCases and controls had similar sex and economic status distributions (Table 1). There were no differences in age between cases and controls; 42 cases (27.1%) and 89 controls (28.7%) were ≥65 years old (OR = 0.92, 95% CI = 0.59–1.42, p = 0.718). The Emergency Room admitted 90 out of 127 cases (70.9%) and 156 out of 243 controls (64.2%), p = 0.197. More cases than controls were hospitalized on the second floor before diagnosis of CDI: 13 out of 86 cases (15.1%) and 10 out of 160 controls (6.3%), p = 0.022. No other differences in spatial distribution within the hospital between cases and controls were found.\n\n10.1371/journal.pone.0198212.t001Table 1 Bivariate analysis of demographic, clinical and environmental variables.\nVariable\tCasesa (n = 155)\tControlsa (n = 310)\tOR\t95% CI\tp\t\nFemale\t84 (54.2)\t170 (54.8)\t0.97\t0.66–1.43\t0.895\t\nAgeb\t55 (38–66)\t52 (37–68)\t1.00\t0.99–1.01\t0.883\t\nEconomic statusc\t2 (2–3)\t2 (2–3)\t1.02\t0.90–1.16\t0.491\t\nCharlson comorbidity index\t4 (2–6)\t4 (2–6)\t0.99\t0.92–1.06\t0.804\t\nTotal length of stayb\t25 (17.5–40)\t10 (6–18)\t—\t—\t<0.001\t\nLength of stay before diagnosisb,\nd\t13 (7.8–20)\t10 (6–18)\t1.01\t0.99–1.02\t0.077\t\nAll-cause death rate upon discharge\t10/154 (6.5)\t25/309 (8.1)\t0.78\t0.36–1.68\t0.540\t\nAll-cause 30-day death rate\t12/149 (8.1)\t31/287 (10.8)\t0.72\t0.36–1.45\t0.361\t\nFebrile neutropenia\t14/148 (9.5)\t5/297 (1.7)\t6.10\t2.15–17.28\t<0.001\t\nLeukemia\t14/148 (9.5)\t14/297 (4.7)\t2.11\t0.97–4.55\t0.052\t\nLymphoma\t12/148 (8.1)\t13/297 (4.4)\t1.92\t0.85–4.33\t0.107\t\nPrevious gastrointestinal surgery\t54/147 (36.7)\t77/292 (26.4)\t1.62\t1.06–2.47\t0.025\t\nIntraabdominal infection\t25/148 (16.9)\t18/297 (6.1)\t3.15\t1.65–5.98\t<0.001\t\nGastrointestinal tract infection\t25/148 (16.9)\t36/297 (12.1)\t1.47\t0.84–2.56\t0.168\t\nNon-gastrointestinal tract infection\t79/148 (53.4)\t124/297 (41.8)\t1.59\t1.07–2.37\t0.020\t\nGastrointestinal tract ostomy\t7/148 (4.7)\t12/297 (4.0)\t1.17\t0.45–3.06\t0.735\t\nLiver transplantation\t4/148 (2.7)\t8/297 (2.7)\t1.0\t0.29–3.38\t1.0\t\nKidney transplantation\t3/148 (2.0)\t20/297 (6.7)\t0.28\t0.08–0.98\t0.035\t\nAutoimmune disease\t12/148 (8.1)\t40/297 (13.5)\t0.56\t0.28–1.11\t0.097\t\nAntineoplastic drugs\t29/147 (19.7)\t37/283 (13.1)\t1.63\t0.95–2.78\t0.069\t\nSystemic steroids\t60/141 (42.6)\t117/277 (42.2)\t1.01\t0.67–1.52\t0.951\t\nImmunosuppressants\t27/145 (18.6)\t56/278 (20.1)\t0.90\t0.54–1.51\t0.708\t\nProton pump inhibitors\t89/134 (66.4)\t144/272 (52.9)\t1.75\t1.14–2.70\t0.010\t\nEnteral nutrition\t18/133 (13.5)\t23/267 (8.6)\t1.66\t0.86–3.19\t0.126\t\nPrevious antibiotic use\t141/147 (95.9)\t230/288 (79.9)e\t5.92\t2.49–14.09\t<0.001\t\nNumber of antibiotics previously usedb\t3 (2–5)\t2 (1–3)\t1.41\t1.25–1.58\t<0.001\t\nAny quinolone\t25/147 (17.0)\t23/275 (8.4)\t2.24\t1.22–4.11\t0.008\t\nCiprofloxacin\t16/147 (10.9)\t6/275 (2.2)\t5.47\t1.97–17.41\t<0.001\t\nMoxifloxacin\t3/147 (2.0)\t11/275 (4.0)\t0.5\t0.09–1.93\t0.396\t\nLevofloxacin\t7/147 (4.8)\t6/275 (2.2)\t2.24\t0.63–8.22\t0.151\t\nMeropenem or imipenem\t66/147 (44.9)\t74/275 (26.9)\t2.21\t1.45–3.36\t<0.001\t\nErtapenem\t53/147 (36.1)\t64/275 (23.3)\t1.85\t1.20–2.88\t0.005\t\nAny carbapenem\t94/147 (63.9)\t118/275 (42.9)\t2.35\t1.53–3.64\t<0.001\t\nVancomycin\t77/147 (52.4)\t98/275 (35.6)\t1.98\t1.32–2.98\t0.001\t\nPiperacillin/ tazobactam\t56/147 (38.1)\t71/275 (25.8)\t1.76\t1.15–2.71\t0.009\t\nCeftriaxone\t34/147 (23.1)\t44/275 (16.0)\t1.58\t0.95–2.60\t0.072\t\nCeftazidime\t5/147 (3.4)\t2/275 (0.7)\t4.80\t0.92–25.08\t0.053\t\nCeftriaxone or ceftazidime\t39/147 (26.5)\t45/275 (16.4)f\t1.84\t1.13–3.0\t0.013\t\nClindamycin\t5/147 (3.4)\t7/275 (2.5)\t1.34\t0.42–4.32\t0.760\t\nDuration of previous antibiotic useb\t12 (7–23)\t3 (0–10)\t1.03\t1.01–1.05\t0.003\t\nPrevious hospitalization\t106/147 (72.1)\t149/281 (53.0)\t2.29\t1.49–3.52\t<0.001\t\nPrevious stay in our hospital\t64/147 (43.5)\t113/281 (40.2)\t1.14\t0.76–1.71\t0.507\t\nReferral from another hospital\t25/147 (17.0)\t24/281 (8.5)\t2.19\t1.20–3.99\t0.009\t\nReferral from another hospital and previous stay in our hospital\t17/147 (11.6)\t12/281 (4.3)\t2.93\t1.36–6.31\t0.004\t\nRoom previously used by case\t26/92 (28.3)\t37/191 (19.4)\t1.64\t0.91–2.92\t0.092\t\nHydrogen peroxide vapor disinfection\t4/94 (4.3)\t10/193 (5.2)\t0.81\t0.24–2.66\t1.0\t\nHO-HCFA CDI, hospital-onset, healthcare facility-associated Clostridium difficile infection; OR, odds ratio; CI, confidence interval.\n\na Absolute frequency (%), unless otherwise stated.\n\nb Median (interquartile range).\n\nc The scale used in the National Health Institutes in Mexico is composed of 6 levels, each one reflecting a different discount rate applied to the hospital discharge bill, as follows: 1 = 96%, 2 = 84%, 3 = 64%, 4 = 43%, 5 = 23%, 6 = 0%.\n\nd Length of stay before diagnosis of CDI (cases) or hospital discharge date (controls).\n\ne Specific antibiotic used for preoperative antibiotic prophylaxis was not mentioned in the charts of 13 control patients.\n\nf One patient used both ceftriaxone and ceftazidime.\n\nTotal length of stay (but not length of stay before diagnosis of CDI) was significantly longer for cases. In-hospital and 30-day mortality rates were similar between cases and controls.\n\nInfecting ribotype information was available for 149 cases; ribotype 027 was identified in 68 cases (45.6%) and non-027 ribotype in 81 cases (54.4%). Exposure to quinolones, ciprofloxacin, moxifloxacin and levofloxacin was stratified by ribotype but no difference was revealed between cases infected with 027 and non-027 strains.\n\nAs shown in Table 1, febrile neutropenia, previous gastrointestinal surgery, intraabdominal infection, non-gastrointestinal tract infection (i.e., infection in any organ system excluding the gastrointestinal tract), previous PPI use, previous antibiotic use, previous hospitalization and referral from another hospital were more frequent in cases. Kidney transplantation was more frequent in controls. An interaction between ciprofloxacin and PPI (hereafter referred to as “exposure to both ciprofloxacin and PPI”) was found (stratified analysis is shown in Table 2), but not for PPI and other quinolones or for PPI and other antibiotics. After multivariable analysis, exposure to both ciprofloxacin and PPI, febrile neutropenia, intraabdominal infection, referral from another hospital and an increasing number of antibiotics used during the hospital stay remained in our model (Table 3).\n\n10.1371/journal.pone.0198212.t002Table 2 Stratified analysis for concomitant use of PPIs and quinolones (ciprofloxacin, moxifloxacin and levofloxacin).\n\t\tCasesa\tControlsa\tOR\t95% CI\tp\t\nQuinolone exposure\tPPI users\t20/88 (22.7)\t16/139 (11.5)\t2.26\t1.03–4.98\t0.024\t\nPPI non-users\t3/43 (7.0)\t6/115 (5.2)\t1.36\t0.21–6.73\t0.704\t\nExposure to both quinolone and PPIb\t20/131 (15.3)\t16/254 (6.3)\t2.68\t1.26–5.74\t0.004\t\nCiprofloxacin exposurec\tPPI users\t13/88 (14.8)\t2/139 (1.4)\t11.87\t2.55–110.02\t<0.001\t\n\tPPI non-users\t1/43 (2.3)\t4/115 (3.5)\t0.66\t0.01–6.94\t1.0\t\nExposure to both ciprofloxacin and PPIb\t13/131 (9.9)\t2/254 (0.8)\t13.88\t3.05–127.79\t<0.001\t\nMoxifloxacin exposure\tPPI users\t2/88 (2.3)\t9/139 (6.5)\t0.33\t0.03–1.68\t0.209\t\nPPI non-users\t1/43 (2.3)\t1/115 (0.01)\t2.71\t0.03–214.88\t0.471\t\nExposure to both moxifloxacin and PPIb\t2/131 (1.5)\t9/254 (3.5)\t0.42\t0.04–2.08\t0.345\t\nLevofloxacin exposure\tPPI users\t6/88 (6.8)\t5/139 (3.6)\t1.96\t0.48–8.36\t0.344\t\nPPI non-users\t1/43 (2.3)\t1/115 (0.01)\t2.71\t0.03–214.88\t0.471\t\nExposure to both levofloxacin and PPIb\t6/131 (4.6)\t5/254 (1.9)\t2.39\t0.59–10.08\t0.195\t\nPPI, proton pump inhibitor; OR, odds ratio; CI, confidence interval.\n\na Absolute frequency (%).\n\nb Exposure to both PPI and quinolone occurred within 3 months before diagnosis of CDI (cases) or the date of hospital discharge (controls). Non-overlapping exposures may have occurred.\n\nc Mantel-Haenszel test of homogeneity was statistically significant (p = 0.035); therefore, an interaction exists between ciprofloxacin and PPI.\n\n10.1371/journal.pone.0198212.t003Table 3 Factors associated with HO-HCFA CDI in logistic regression analysis.\nVariable\taOR\t95% CI\tCoefficient\tp\t\nExposure to both ciprofloxacin and PPI\t8.07\t1.70–38.16\t2.09\t0.008\t\nFebrile neutropenia\t4.61\t1.37–15.46\t1.53\t0.013\t\nIntraabdominal infection\t2.06\t0.95–4.46\t0.73\t0.064\t\nReferral from other hospital\t1.99\t0.98–4.05\t0.69\t0.056\t\nIncreasing number of antibiotics previously used\t1.28a\t1.13–1.46\t0.25\t<0.001\t\nConstant for the model = 0.20 (95% CI = 0.13–0.30).\n\nHO-HCFA CDI, hospital onset, healthcare facility-associated Clostridium difficile infection; aOR, adjusted odds ratio; CI, confidence interval; PPI, proton pump inhibitor.\n\na aOR for every increase in the number of antibiotics previously used.\n\nMedian CDI pressure values for cases and controls were 1.74 (IQR = 0.96–5.41) and 1.58 (IQR = 0.71–4.67), respectively (p = 0.539).\n\nAnalysis of hospital-wide broad-spectrum antibiotic consumption from 2012 to 2016 revealed a mixed trend for quinolones (reduction from 834 DDD in 2012 to 161 DDD in 2015, but an increase to 294 DDD in 2016 that coincided with the outbreak), a slight increasing trend for carbapenems and vancomycin, and a steady trend for piperacillin/tazobactam and ceftriaxone. Detailed results are shown in Fig 2. Clindamycin consumption was below 10 DDD per 1,000 patient-days for any given year and therefore, was not plotted.\n\n10.1371/journal.pone.0198212.g002Fig 2 Antibiotic consumption (DDD per 1,000 patient-days per year, 2012–2016).\nDiscussion\nThis study showed that the main factors associated with the first episode of HO-HCFA CDI in the setting of an outbreak in our hospital were exposure to both ciprofloxacin and PPI, febrile neutropenia, an increase in the number of antibiotics used before the CDI episode, intraabdominal infection and referral from other hospitals. Although the former two variables had p values above 0.05, they fulfilled our predefined statistical criteria (p<0.1) and are also biologically plausible and significant.\n\nIn our setting, previous exposure to systemic antibiotics is a major factor associated with HO-HCFA CDI and risk varies by antibiotic class, as has been demonstrated by others [20–24]. In particular, ciprofloxacin showed the greatest association in combination with PPI, as has been described previously [25]. One postulated mechanism is that the PPI may alter the absorption of antibiotics, resulting in a greater concentration of the latter in the intestinal lumen [26]; however, this hypothesis has not been confirmed. As stated by others [20–27], we found that carbapenems, third generation cephalosporins, piperacillin/tazobactam and vancomycin were associated with HO-HCFA CDI, although only in bivariate analysis. Finally, the association between an increasing number of antibiotics previously used and CDI was described in a previous study done in our hospital and was confirmed in the present one [3].\n\nThe analysis of hospital-wide broad-spectrum antibiotic use revealed a steep increase in quinolone consumption between 2015 and 2016 after a declining tendency in previous years (as opposed to declining or stable tendencies for the other antibiotics). Although renewed efforts to reduce quinolone consumption in the hospital are underway and are undoubtedly needed, the majority of patients treated with quinolones had received at least one dose before being admitted to our hospital; therefore, efforts in our hospital should also be paralleled by efforts at the community level to achieve a reduction of cases of CDI. [28]\n\nSome differences between our study and others were noted. Increasing age is one of the most consistently cited risk factors for CDI, but our study, in agreement with other reports [3–6], did not find such an association. Differences in CDI pressure values between cases and controls were not reproduced in our study due to the fact that the value for controls in our study was substantially higher than that reported elsewhere [17]. Great efforts were devoted to discharge stable and uncomplicated CDI cases for ambulatory treatment as early as possible in an attempt to reduce CDI pressure values, but many patients remained hospitalized due to other comorbidities. Although CDI pressure values for cases and controls were similar in our study, the appearance of new HO-HCFA CDI cases in close spatial and temporal proximity to others suggests cross-transmission may have occurred (see S1 File). In our consideration, this graphical analysis is a way of depicting the influence the environment has had on this outbreak, despite the fact that statistical results do not fully support this observation.\n\nThe fact that referral from another hospital was associated with HO-HCFA CDI may be a plausible explanation for outbreak persistence despite commonplace infection control measures in our hospital. One hypothesis is that referral from another hospital is a marker of environmental exposure to C. difficile; this hypothesis is supported by previous studies that showed that CDI rates in neighboring referral hospitals were correlated with those of hospitals from which the patients were transferred [11, 12]. In fact, screening of high-risk patients upon admission (including those with previous hospital admissions) has been recently suggested as an adjunct measure for control of CDI in hospitals [29].\n\nOur study has strengths. This is an updated report of factors associated with CDI in the setting of an outbreak in a Mexican hospital. It included a broad range of hospitalized patients with different comorbidities and information about many associated factors and confounders, better reflecting the real scenario in our hospital. It has also shown that some associated factors could be particular to our hospital, a fact that better emphasizes the need to perform research in different clinical settings [30]. Additionally, the results may help to develop and validate a predictive score to identify patients at risk for HO-HCFA CDI upon admission to our hospital, in an attempt to shift the prevailing prevention paradigm from a secondary prevention strategy to a primary prevention one.\n\nWe acknowledge limitations. Missing data could not be recovered for many environmental variables not registered in charts. We could not analyze the impact of the preventive strategies as a whole on HO-HCFA CDI rates since we were only able to measure adherence to hand hygiene and hydrogen peroxide vapor use. Differentiation of adherence to hand hygiene with soap and water or alcohol hand rub was not possible, although a separate surrogate analysis is offered (S4 File); despite concerns that the alcohol hand rub is not able to eliminate spores, its use is nonetheless not contraindicated in hospital outbreaks of CDI, as stated in the updated 2017 guidelines [31]. Molecular analyses of C. difficile strains isolated during the outbreak are still pending and could undoubtedly aid in the interpretation of transmission dynamics.\n\nConclusions\nThe factors found to be independently associated with the first episode of HO-HCFA CDI during an outbreak in a tertiary referral hospital in Mexico were exposure to both ciprofloxacin and PPI, febrile neutropenia, intraabdominal infection, referral from another hospital and an increasing number of antibiotics previously used. Patients referred to us from other hospitals could be asymptomatic carriers of C. difficile, and this might be an interesting research subject in Mexico.\n\nSupporting information\nS1 File Graphical representation of temporal and spatial evolution of the outbreak within the hospital.\n(PDF)\n\nClick here for additional data file.\n\n S2 File Database.\n(XLSX)\n\nClick here for additional data file.\n\n S3 File Interaction analysis and simplified model-building strategy.\n(PDF)\n\nClick here for additional data file.\n\n S4 File Audit of chlorhexidine soap and alcohol hand rub consumption, 2015–2016.\n(PDF)\n\nClick here for additional data file.\n\n We are indebted to the following persons: Anri Pérez-Nakano and Christopher Ruben-Castillo (data collection), Ricardo González-González (edition of figures), Jorge López-Pérez (codification of hospital discharge diagnoses), Elia Criollo-Mora (antibiotic consumption data), and Deborah H. S. (proofreading of the article).\n==== Refs\nReferences\n1 Depestel DD , Aronoff DM . Epidemiology of Clostridium difficile infection . J Pharm Pract \n2013 ;26 :464 –475 . doi: 10.1177/0897190013499521 \n24064435 \n2 Lessa FC , Mu Y , Bamberg WM , et al\nBurden of Clostridium difficile infection in the United States . N Engl J Med \n2015 ;372 :825 –834 . doi: 10.1056/NEJMoa1408913 \n25714160 \n3 Camacho-Ortiz A , Galindo-Fraga A , Rancel-Cordero A , et al [Factors associated with Clostridium difficile disease in a tertiary-care medical institution in Mexico: a case-control study ]. Rev Invest Clin \n2009 ;61 :371 –377 . 20184096 \n4 Morfin-Otero R , Garza-Gonzalez E , Aguirre-Diaz SA , et al.\nClostridium difficile outbreak caused by NAP1/BI/027 strain and non-027 strains in a Mexican hospital . Braz J Infect Dis \n2016 ;20 :8 –13 . doi: 10.1016/j.bjid.2015.09.008 \n26620948 \n5 Camacho-Ortiz A , López-Barrera D , Hernández-García R , et al\nFirst report of Clostridium difficile NAP1/027 in a Mexican hospital . PLoS One \n2015 \n4 \n27 ;10 (4 ):e0122627 \ndoi: 10.1371/journal.pone.0122627 \n25915544 \n6 Menéndez M , Batista N , Bálsamo A , Seija V . Predictores de riesgo para desarrollo de infección por Clostridium difficile . Revista Médica del Uruguay \n2016 ;32 :159 –165 . Spanish.\n7 Kim KH , Fekety R , Batts DH , et al\nIsolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis . J Infect Dis \n1981 ;143 :42 –50 . 7217711 \n8 Garcia C , Samalvides F , Vidal M , Gotuzzo E , Dupont HL . Epidemiology of Clostridium difficile-associated diarrhea in a Peruvian tertiary care hospital . Am J Trop Med Hyg \n2007 ;77 :802 –805 . 17984329 \n9 Weber DJ , Anderson DJ , Sexton DJ , Rutala WA . Role of the environment in the transmission of Clostridium difficile in health care facilities . Am J Infect Control \n2013 ;41 (5 Suppl ):S105 –S110 . doi: 10.1016/j.ajic.2012.12.009 \n23622740 \n10 García-Lecona DA , Garza-González E , Padilla-Orozco M , et al\nOutcomes of Clostridium difficile-infected patients managed in a common isolation unit compared with isolation in their bed of diagnosis . Am J Infect Control \n2017 \n7 \n25 pii: S0196-6553(17)30779-4. doi: 10.1016/j.ajic.2017.06.006 \n28754222 \n11 Simmering JE , Polgreen LA , Campbell DR , Cavanaugh JE , Polgreen PM . Hospital transfer network structure as a risk factor for Clostridium difficile infection . Infect Control Hosp Epidemiol \n2015 ;36 :1031 –1037 . doi: 10.1017/ice.2015.130 \n26072907 \n12 Fernández-Gracia J , Onnela JP , Barnett ML , Eguíluz VM , Christakis NA . Influence of a patient transfer network of US inpatient facilities on the incidence of nosocomial infections . Sci Rep \n2017 ;7 :2930 \ndoi: 10.1038/s41598-017-02245-7 \n28592870 \n13 Cohen SH , Gerding DN , Johnson S , et al\nClinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) . Infect Control Hosp Epidemiol \n2010 ;31 :431 –455 . doi: 10.1086/651706 \n20307191 \n14 Lewis SJ , Heaton KW . Stool form scale as a useful guide to intestinal transit time . Scand J Gastroenterol \n1997 ;32 :920 –924 . doi: 10.3109/00365529709011203 \n9299672 \n15 Tamez-Torres KM , Torres-González P , Leal-Vega F , García-Aldrete A , López-García NI , Mendoza-Aguilar R , et al\nImpact of Clostridium difficile infection caused by the NAP1/RT027 strain on severity and recurrence during an outbreak and transition to endemicity in a Mexican tertiary care center . Int J Infect Dis \n2017 ;65 :44 –49 . doi: 10.1016/j.ijid.2017.09.022 \n28986313 \n16 International Statistical Classification of Diseases and Related Health Problems, 10th Revision [Internet]. World Health Organization; c2016 [cited 2018 Apr 06]. Available from: http://www.who.int/classifications/icd/icdonlineversions/en/\n17 Dubberke ER , Reske KA , Olsen MA , et al\nEvaluation of Clostridium difficile-associated disease pressure as a risk factor for C. difficile-associated disease . Arch Intern Med \n2007 ;167 :1092 –1097 . doi: 10.1001/archinte.167.10.1092 \n17533213 \n18 ATC/DDD Index 2017. WHO Collaborating Centre for Drug Statistics Methodology. Available from: https://www.whocc.no/atc_ddd_index/\n19 Hosmer DW , Lemeshow S , Sturdivant RX . Applied Logistic Regression . 3rd ed. \nHoboken : John Wiley & Sons, Inc ; c2013 Chapter 4, Model-building strategies and methods for logistic regression; p. 89 –151 .\n20 Brown KA , Khanafer N , Daneman N , Fisman DN . Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection . Antimicrob Agents Chemother \n2013 ;57 :2326 –2332 . doi: 10.1128/AAC.02176-12 \n23478961 \n21 Owens RC Jr, Donskey CJ , Gaynes RP , Loo VG , Muto CA . Antimicrobial-associated risk factors for Clostridium difficile infection . Clin Infect Dis \n2008 ;46 (Suppl 1 ):S19 –S31 .18177218 \n22 Bignardi GE . Risk factors for Clostridium difficile infection . J Hosp Infect \n1998 ;40 :1 –15 . 9777516 \n23 Aldrete S del M , Magee MJ , Friedman-Moraco RJ , et al\nCharacteristics and antibiotic use associated with short-term risk of Clostridium difficile infection among hospitalized patients . Am J Clin Pathol \n2015 ;143 :895 –900 . doi: 10.1309/AJCP9EWI6QPVTPQY \n25972333 \n24 Chung P , Currie B , Guo Y , Talansky M , Brown S , Ostrowsky B . Investigation to identify a resource-efficient case-control methodology for determining antibiotics associated with Clostridium difficile infection . Am J Infect Control \n2014 ;42 (10 Suppl ):S264 –S268 . doi: 10.1016/j.ajic.2014.05.001 \n25239720 \n25 Gordon D , Young LR , Reddy S , Bergman C , Young JD . Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor . J Hosp Infect \n2016 ;92 :173 –177 . doi: 10.1016/j.jhin.2015.10.009 \n26616410 \n26 Stevens V , Dumyati G , Brown J , Wijngaarden E . Differential risk of Clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure . Pharmacoepidemiol Drug Saf \n2011 ;20 :1035 –1042 . doi: 10.1002/pds.2198 \n21833992 \n27 Lin HJ , Hung YP , Liu HC , et al\nRisk factors for Clostridium difficile-associated diarrhea among hospitalized adults with fecal toxigenic C. difficile colonization . J Microbiol Immunol Infect \n2015 ;48 :183 –189 . doi: 10.1016/j.jmii.2013.08.003 \n24064285 \n28 Dingle KE , Didelot X , Quan TP , Eyre DW , Stoesser N , Golubchik T , et al\nEffects of control interventions on Clostridium difficile infection in England: an observational study . Lancet Infect Dis \n2017 ;17 :411 –421 . doi: 10.1016/S1473-3099(16)30514-X \n28130063 \n29 Caroff DA , Yokoe DS , Klompas M . Evolving insights into the epidemiology and control of Clostridium difficile in hospitals . Clin Infect Dis \n2017 \n5 \n17 \ndoi: 10.1093/cid/cix456 \n28520953 \n30 Dubberke ER , Yan Y , Reske KA , et al\nDevelopment and validation of a Clostridium difficile infection risk prediction model . Infect Control Hosp Epidemiol \n2011 ;32 :360 –366 . doi: 10.1086/658944 \n21460487 \n31 McDonald LC , Gerding DN , Johnson S , Bakken JS , Carroll KC , Coffin SE , et al\nClinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) . Clin Infect Dis \n2018 ;66 :e1 –e48 . doi: 10.1093/cid/cix1085 \n29462280\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "13(5)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003428:Cross Infection; D004196:Disease Outbreaks; D004777:Environment; D005260:Female; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D062606:Tertiary Care Centers",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0198212",
"pmc": null,
"pmid": "29813115",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "25239720;9777516;7217711;28986313;26072907;21833992;28754222;23478961;28592870;20184096;24064435;25972333;18177218;23622740;29462280;26616410;21460487;24064285;28520953;17984329;20307191;25714160;17533213;28130063;26620948;25915544;9299672",
"title": "Factors associated with an outbreak of hospital-onset, healthcare facility-associated Clostridium difficile infection (HO-HCFA CDI) in a Mexican tertiary care hospital: A case-control study.",
"title_normalized": "factors associated with an outbreak of hospital onset healthcare facility associated clostridium difficile infection ho hcfa cdi in a mexican tertiary care hospital a case control study"
} | [
{
"companynumb": "MX-BAYER-2018-114248",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
"... |
{
"abstract": "Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one-year-old child with a life-threatening GI-aGvHD stage IV, post-HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta-derived DSC.",
"affiliations": "Department of Clinical Intervention and Technology, CLINTEC, Karolinska Institutet, Stockholm, Sweden.;Department of Women's and Children's Health, Pediatric Oncology, Children's University Hospital, Uppsala, Sweden.;Department of Pathology and Cytologi, Karolinska University Hospital, Stockholm, Sweden.;Department of Laboratory Medicine, Division of Therapeutic Immunology, Karolinska Institutet, Stockholm, Sweden.;Department of Laboratory Medicine, Division of Therapeutic Immunology, Karolinska Institutet, Stockholm, Sweden.;Department of Women's and Children's Health, Pediatric Oncology, Children's University Hospital, Uppsala, Sweden.",
"authors": "Gustafsson|Britt|B|http://orcid.org/0000-0002-7080-5053;Frisk|Per|P|;Szakos|Attilla|A|;Sadeghi|Behnam|B|;Ringdén|Olle|O|;Frost|Britt-Marie|BM|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12990",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(5)",
"journal": "Pediatric transplantation",
"keywords": "acute graft-versus-host disease; decidual stromal cells; pediatric allogeneic hematopoietic stem cell transplantation; steroid-refractory gastrointestinal bleedings",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000208:Acute Disease; D005260:Female; D005767:Gastrointestinal Diseases; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D010920:Placenta; D011247:Pregnancy",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28612364",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment with placenta-derived decidual stromal cells in a pediatric patient with life-threatening acute gastrointestinal graft-versus-host disease.",
"title_normalized": "successful treatment with placenta derived decidual stromal cells in a pediatric patient with life threatening acute gastrointestinal graft versus host disease"
} | [
{
"companynumb": "PHHY2017SE128164",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TREOSULFAN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma patients who are eligible to receive high-dose therapy, recognizing that the optimal timing and integration of this approach is now under study in a number of randomized trials. Despite the improved response rates with induction therapy consisting of immunomodulatory drugs and/or proteasome inhibitors, as well as the increasing use of post-ASCT maintenance therapy, most myeloma patients relapse and die of their disease. Here we discuss the options for managing post-ASCT relapse, including the role of various salvage regimens in the setting of relapsed and refractory myeloma, salvage ASCT, and salvage allogeneic SCT.",
"affiliations": "Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.;Department of Hematologic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.;Department of Hematologic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.;Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York. Electronic address: plmcc54@gmail.com.",
"authors": "Holstein|Sarah A|SA|;Richardson|Paul G|PG|;Laubach|Jacob P|JP|;McCarthy|Philip L|PL|",
"chemical_list": "D007155:Immunologic Factors; D061988:Proteasome Inhibitors; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "21(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Monoclonal antibody; Multiple myeloma salvage autologous stem cell transplant; Relapsed/refractory; Salvage allogenic stem cell transplant",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D064592:Autografts; D003907:Dexamethasone; D006801:Humans; D007155:Immunologic Factors; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D061988:Proteasome Inhibitors; D012008:Recurrence; D033581:Stem Cell Transplantation; D013792:Thalidomide",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "793-8",
"pmc": null,
"pmid": "25652690",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Management of relapsed multiple myeloma after autologous stem cell transplant.",
"title_normalized": "management of relapsed multiple myeloma after autologous stem cell transplant"
} | [
{
"companynumb": "PHHY2015US026694",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Atrial fibrillation (AF) is one of the most common cardiac arrhythmias in the adult population. Propafenone is a class 1c antiarrhythmic agent that has an electrophysiologic profile suggesting that it might be potentially effective in recent-onset AF. The present study was undertaken, therefore, to examine the time course as well as the frequency of successful conversion in patients with recent-onset AF treated with propafenone administered orally. Fifty patients with recent-onset AF were recruited into 2 groups: 25 patients were given propafenone, 150 mg every 4 h, and 25 patients served as a control group and received verapamil (a drug known to slow the ventricular response but not to restore sinus rhythm) 40 mg, every 4 h and up to 48 h or until conversion to sinus rhythm occurred. Of the 50 patients, 2 refused to continue the study and another 2 were excluded because of left heart failure. Conversion to sinus rhythm occurred in 21 of 24 patients (87 percent) in the propafenone group as compared with 9 of 22 (41 percent) in the verapamil group (p < 0.001). In 10 patients in the propafenone group, conversion occurred within 12 h, within 24 h in another 9 patients, and between 24 and 48 h in the remaining 2 patients. There was no correlation between the duration of AF prior to entry into the study and the subsequent incidence of and time to conversion with propafenone. With respect to cause of AF, all groups showed a high incidence of conversion. Two patients developed heart failure during treatment and one patient (in the verapamil group) developed embolic stroke while still having atrial fibrillation. We conclude that in patients with AF, the prognosis for conversion to sinus rhythm within 48 h, with propafenone, is excellent (87 percent) and safe.",
"affiliations": "Department of Medicine A, Hillel Yaffe Medical Center, Hadera, Israel.",
"authors": "Weiner|P|P|;Ganam|R|R|;Ganem|R|R|;Zidan|F|F|;Rabner|M|M|",
"chemical_list": "D011405:Propafenone; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": "10.1378/chest.105.4.1013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "105(4)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D001281:Atrial Fibrillation; D006339:Heart Rate; D006801:Humans; D008875:Middle Aged; D011405:Propafenone; D014700:Verapamil",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "1013-6",
"pmc": null,
"pmid": "8162718",
"pubdate": "1994-04",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Clinical course of recent-onset atrial fibrillation treated with oral propafenone.",
"title_normalized": "clinical course of recent onset atrial fibrillation treated with oral propafenone"
} | [
{
"companynumb": "IL-RECRO GAINESVILLE LLC-REPH-2019-000089",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"... |
{
"abstract": "OBJECTIVE\nThe study objective was to examine the safety and cost savings of selective cardiac surveillance (CS) during treatment with pegylated liposomal doxorubicin (PLD).\n\n\nMETHODS\nA retrospective, dual institution study of women receiving PLD for the treatment of a gynecologic malignancy was performed. The study period was 2002-2014. At both institutions, a selective strategy for CS was implemented in which only high-risk women with a cardiac history or with symptoms suggestive of cardiac toxicity during PLD treatment underwent a cardiac evaluation. Patient demographics, clinical and treatment history were evaluated. Cost analyses were performed utilizing professional/technical fee rates for echocardiogram and multi-gated acquisition scan for each state.\n\n\nRESULTS\nPLD was administered in 184 women. The mean patient age was 62.7years, and 79% were treated for recurrent ovarian or peritoneal carcinoma. The median cumulative administered dose of PLD was 300mg/m(2); 24 received >550mg/m(2). The median follow-up time was 20months. Of the 184 patients, the majority (n=157, 85.3%) did not undergo either an initial cardiac evaluation or surveillance during or post-PLD treatment. Fifty-three patients considered high risk for anthracycline-induced cardiotoxicity underwent CS. Only three patients (1.6%) in the entire cohort developed CHF that was possibly related to PLD treatment; all had significant pre-existing cardiac risk factors. Selective instead of routine use of CS in the study population resulted in a cost savings of $182,552.28.\n\n\nCONCLUSIONS\nUtilizing cardiac surveillance in select women undergoing PLD treatment for gynecologic malignancies resulted in significant health care cost savings without adversely impacting clinical outcomes.",
"affiliations": "The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Duke University Medical Center, Durham, NC, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Duke University Medical Center, Durham, NC, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, MD, United States. Electronic address: afader1@jhmi.edu.",
"authors": "Kushnir|C L|CL|;Angarita|A M|AM|;Havrilesky|L J|LJ|;Thompson|S|S|;Spahlinger|D|D|;Sinno|A K|AK|;Tanner|E J|EJ|;Secord|A A|AA|;Roche|K L|KL|;Stone|R L|RL|;Fader|A N|AN|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "137(3)",
"journal": "Gynecologic oncology",
"keywords": "Cardiotoxicity; Echocardiogram; Gynecologic malignancy; Pegylated liposomal doxorubicin; Surveillance",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D066126:Cardiotoxicity; D015331:Cohort Studies; D003365:Costs and Cost Analysis; D004317:Doxorubicin; D004452:Echocardiography; D005260:Female; D005833:Genital Neoplasms, Female; D006801:Humans; D008875:Middle Aged; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "503-7",
"pmc": null,
"pmid": "25735254",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD).",
"title_normalized": "selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin pld"
} | [
{
"companynumb": "US-JNJFOC-20150603937",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc-positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis.\n\n\n\nThirty-three HBsAg-negative/anti-HBc-positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1-8) over 34 months (range 0-80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated.\n\n\n\nNone of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs-negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0-70) after RTX discontinuation, no HBV reactivation was observed.\n\n\n\nThe administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.",
"affiliations": "From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco.;From the Rheumatology Unit, Ospedale L. Sacco; Hepatology Unit, Ospedale San Giuseppe, University of Milan; A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Rheumatology Day Hospital, Istituto Ortopedico G. Pini, Milan; Rheumatology Unit, Ospedale Mauriziano, Turin; Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia, Pavia; University Rheumatology Department, Azienda Ospedaliero Universitaria (AOU) Policlinico, Bari, Italy.V. Varisco*, MD, Rheumatology Unit, Ospedale L. Sacco; M. Viganò*, MD, Hepatology Unit, Ospedale San Giuseppe, University of Milan; A. Batticciotto, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Lampertico, MD, PhD, Professor, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; A. Marchesoni, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; P. Gibertini, MD, Rheumatology Day Hospital, Istituto Ortopedico G. Pini; R. Pellerito, MD, Rheumatology Unit, Ospedale Mauriziano; G. Rovera, MD, Rheumatology Unit, Ospedale Mauriziano; R. Caporali, MD, Professor, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Todoerti, MD, Rheumatology Division, IRCCS Fondazione San Matteo, Università di Pavia; M. Covelli, MD, University Rheumatology Department, AOU Policlinico; A. Notarnicola, MD, University Rheumatology Department, AOU Policlinico; F. Atzeni, MD, PhD, Rheumatology Unit, Ospedale L. Sacco; P. Sarzi-Puttini, MD, Rheumatology Unit, Ospedale L. Sacco. sarzi.piercarlo@hsacco.it.",
"authors": "Varisco|Valentina|V|;Viganò|Mauro|M|;Batticciotto|Alberto|A|;Lampertico|Pietro|P|;Marchesoni|Antonio|A|;Gibertini|Patrizia|P|;Pellerito|Raffaele|R|;Rovera|Guido|G|;Caporali|Roberto|R|;Todoerti|Monica|M|;Covelli|Michele|M|;Notarnicola|Antonella|A|;Atzeni|Fabiola|F|;Sarzi-Puttini|Piercarlo|P|",
"chemical_list": "D018501:Antirheumatic Agents; D000069283:Rituximab",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.151105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "43(5)",
"journal": "The Journal of rheumatology",
"keywords": "HBV DNA; HBsAg; HEPATITIS B VIRUS REACTIVATION; RHEUMATOID ARTHRITIS; RITUXIMAB",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004359:Drug Therapy, Combination; D005260:Female; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D014775:Virus Activation",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "869-74",
"pmc": null,
"pmid": "26879359",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc-positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study.",
"title_normalized": "low risk of hepatitis b virus reactivation in hbsag negative anti hbc positive carriers receiving rituximab for rheumatoid arthritis a retrospective multicenter italian study"
} | [
{
"companynumb": "IT-PFIZER INC-2018012862",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHeart transplant (HT) recipients are at risk for invasive fungal disease (IFD), a morbid and potentially fatal complication.\n\n\nMETHODS\nWe performed a retrospective cohort study to evaluate the incidence and risk factors for IFD in HT recipients from 1995 to 2012 at a single center. IFD cases were classified as proven or probable IFD according to current consensus definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. We calculated IFD incidence rates and used Cox proportional hazards models to determine IFD risk factors.\n\n\nRESULTS\nThree hundred sixty patients underwent HT during the study period. The most common indications were dilated (39%) and ischemic (37%) cardiomyopathy. There were 23 (6.4%) cases of proven (21) or probable (2) IFD, for a cumulative incidence rate of 1.23 per 100 person-years (95% CI 0.78 to 1.84). Candida (11) and Aspergillus (5) were the most common etiologic fungi. Thirteen cases (56%) occurred within 3 months of HT, with a 3-month incidence of 3.8% (95% CI 2.2 to 6.4). Delayed chest closure (HR 3.3, 95% CI 1.4 to 7.6, p = 0.01) and the addition of OKT3, anti-thymocyte globulin or daclizumab to standard corticosteroid induction therapy (HR 2.7, 95% CI 1.1 to 6.2, p = 0.02) were independently associated with an increased risk of IFD.\n\n\nCONCLUSIONS\nIFD incidence was greatest within the first 3 months post-HT, largely reflecting early surgical-site and nosocomial Candida and Aspergillus infections. Patients receiving additional induction immunosuppression or delayed chest closure were at increased risk for IFD. Peri-transplant anti-fungal prophylaxis should be considered in this subset of HT recipients.",
"affiliations": "Division of Infectious Diseases. Electronic address: arabin@partners.org.;Cardiovascular Division.;Division of Cardiac Surgery, Brigham and Women's Hospital, Boston, Massachusetts.;Division of Infectious Diseases.;Division of Infectious Diseases.;Division of Infectious Diseases.;Division of Infectious Diseases.;Division of Infectious Diseases.;Division of Infectious Diseases.",
"authors": "Rabin|Alexander S|AS|;Givertz|Michael M|MM|;Couper|Gregory S|GS|;Shea|Margaret M|MM|;Peixoto|Driele|D|;Yokoe|Deborah S|DS|;Baden|Lindsey R|LR|;Marty|Francisco M|FM|;Koo|Sophia|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "34(2)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "Aspergillus; Candida; heart transplantation; invasive fungal disease; risk factors",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D008297:Male; D008404:Massachusetts; D008875:Middle Aged; D009181:Mycoses; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D066027:Transplant Recipients; D055815:Young Adult",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "227-32",
"pmc": null,
"pmid": "25455750",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20218876;16297770;21323827;23921444;24559945;10919584;11428994;12751263;12975755;15023157;3619541;18462102;18552253;20970596;8623160;8507760;1420232;3058911",
"title": "Risk factors for invasive fungal disease in heart transplant recipients.",
"title_normalized": "risk factors for invasive fungal disease in heart transplant recipients"
} | [
{
"companynumb": "US-JNJFOC-20150219632",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThromboembolic events (TE) are common in patients with cancer and are potentially life-threatening. In lung cancer, little is known about thrombosis during chemotherapy treatment. The aim of this study was to describe the incidence of TE in patients with non-small cell lung cancer (NSCLC), occurring during treatment with platinum-based chemotherapy.\n\n\nMETHODS\nWe retrospectively selected patients with NSCLC treated with platinum-based chemotherapy at the VU University Medical Center Amsterdam between 2000 and 2012. Patients who underwent recent surgery were excluded. All TE were included that occurred from start of chemotherapy treatment until 30 days after last administration.\n\n\nRESULTS\nAmong 784 included patients, 63 (8.0%) patients had 69 TE during treatment. Forty-five venous TE (VTE) and 24 arterial TE (ATE). Six patients had multiple events within treatment period, 3 of which had simultaneous ATE and VTE. In total, 613 patients were treated with cisplatin, 119 patients received carboplatin and 52 patients received both in first- or second-line treatment. In 8% (55/665) of the patients exposed to cisplatin a TE had occurred vs. 5% (8/171) in patients exposed to carboplatin (p=0.42). The majority of TE occurred in the first 2 cycles (70%). History of TE was related to occurrence of TE during chemotherapy (p<0.01). Median PFS was similar in patients with and without TE (6.2 vs. 7.2 months, respectively; p=0.10). Median OS was significantly shorter in patients with TE (9.5 vs. 12.9 months, respectively; p=0.03).\n\n\nCONCLUSIONS\nIn our series, both ATE and VTE were a common finding during chemotherapy. TE was a poor prognostic factor. No difference in TE incidence was found between patients treated with cisplatin or carboplatin.",
"affiliations": "Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Electronic address: ef.smit@vumc.nl.",
"authors": "Mellema|Wouter W|WW|;van der Hoek|Dorien|D|;Postmus|Pieter E|PE|;Smit|Egbert F|EF|",
"chemical_list": "D010984:Platinum",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "86(1)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Arterial thromboembolic event (ATE); Carboplatin; Cisplatin; Non-small cell lung carcinoma; Platinum chemotherapy; Thrombosis; Venous thromboembolic event (VTE)",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010984:Platinum; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "73-7",
"pmc": null,
"pmid": "25129368",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective evaluation of thromboembolic events in patients with non-small cell lung cancer treated with platinum-based chemotherapy.",
"title_normalized": "retrospective evaluation of thromboembolic events in patients with non small cell lung cancer treated with platinum based chemotherapy"
} | [
{
"companynumb": "NL-HQ SPECIALTY-NL-2015INT000603",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Injections of botulinum toxin are widely used in different medical fields, namely neurology, urology, stomatology, cosmetology, gastroenterology etc. Preparations of botulinum toxin type A (BTA) prevent the release of acetylcholine at the endings of motor nerves leading to the long-term muscle relaxation. It has been acknowledged that treatment with BTA has very good safety profile and tolerability. Extremely rare but severe complication of botulinotherapy (BT) is a condition, which is associated with generalized muscle Weakness, swallowing difficulty, respiratory arrest, and may lead to the lethal outcomes in the solitary cases. Such disorders, which present like botulism, are known as botulism-like syndrome and iatrogenic botulism. We report a clinical case of such complication in the paper. The probability of the development of such rare but severe complications necessitates certain awareness and vigilance among clinicians performing BT.",
"affiliations": "Bashkir State Medical University, Ufa, Bashkortostan, Russia.;Bashkir State Medical University, Ufa, Bashkortostan, Russia.",
"authors": "Ibatullin|R A|RA|;Magjanov|R V|RV|",
"chemical_list": "D019274:Botulinum Toxins, Type A",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.26442/terarkh20189011102-104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3660",
"issue": "90(11)",
"journal": "Terapevticheskii arkhiv",
"keywords": "botulinotherapy; botulism-like syndrome; complications; iatrogenic botulism",
"medline_ta": "Ter Arkh",
"mesh_terms": "D019274:Botulinum Toxins, Type A; D001906:Botulism; D006801:Humans; D007049:Iatrogenic Disease; D012131:Respiratory Insufficiency; D013577:Syndrome",
"nlm_unique_id": "2984818R",
"other_id": null,
"pages": "102-104",
"pmc": null,
"pmid": "30701823",
"pubdate": "2018-11-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of iatrogenic botulism after botulinotherapy in clinical practice.",
"title_normalized": "case of iatrogenic botulism after botulinotherapy in clinical practice"
} | [
{
"companynumb": "RU-ALLERGAN-1902590US",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null... |
{
"abstract": "Methotrexate is a commonly used agent in the treatment of an un-ruptured ectopic pregnancy. Thromboembolic events are rarely seen side effects of such a medicine. We report the case of the 22-year-old woman who underwent Methotrexate therapy for an un-ruptured ectopic pregnancy without any history of thromboembolic risk factors. A second dose (50 mg/m2) was administered to the patient showing a nondecreasing pattern of β-HCG levels after an initial standard dosage of Methotrexate (50 mg/m2). On the 12th day of the treatment, a sudden onset of painless vision loss was seen in the right eye. Fundal imaging and fluorescein angiography revealed an occlusion of the superior temporal branch of the right retinal artery. After a month of hyperbaric oxygen therapy, complete recovery without loss of vision was achieved.",
"affiliations": "Department of Obstetrics and Gynecology, Kocaeli University School of Medicine, Kocaeli, Turkey.;Department of Obstetrics and Gynecology, Sanliurfa Training and Research Hospital, Yenice Mananes No. 1 Eyyubiyc, Sanliurfa, Turkey.;Department of Obstetrics and Gynecology, Kocaeli University School of Medicine, Kocaeli, Turkey.;Department of Obstetrics and Gynecology, Kocaeli University School of Medicine, Kocaeli, Turkey.",
"authors": "Gezer|Sener|S|;Vural|Birol|B|;Kirsavoglu|Mehtap|M|;Cakiroglu|Yigit|Y|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D008727:Methotrexate",
"country": "Pakistan",
"delete": false,
"doi": "10.5455/JPMA.14284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-9982",
"issue": "70(2)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": " Methotrexate, Ectopic pregnancy, Branch retinal artery occlusion.\n ",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D006931:Hyperbaric Oxygenation; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D015356:Retinal Artery Occlusion; D019233:Retreatment; D041623:Tomography, Optical Coherence; D014786:Vision Disorders; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "357-359",
"pmc": null,
"pmid": "32063635",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Branch retinal artery occlusion in a patient undergoing Methotrexate therapy for ectopic pregnancy: A case report.",
"title_normalized": "branch retinal artery occlusion in a patient undergoing methotrexate therapy for ectopic pregnancy a case report"
} | [
{
"companynumb": "TR-PFIZER INC-2021000454",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "Donor-derived infections (DDIs) are a very rare but potentially devastating complication of solid organ transplantation. Here we present a cluster of proven donor-derived cryptococcal infection in the kidney, liver, and lung recipients from a single donor. Remarkably, the onset of illness in the kidney and liver recipients occurred more than 8-12 weeks after transplantation, which is beyond the incubation period previously reported for donor-derived cryptococcosis. DDI should always be considered in the differential diagnosis of transplant recipients admitted with febrile illness, even when presenting beyond the first month post-transplant. Communication between reference laboratories, transplant centers, and organ procurement organizations is critical to improve outcomes.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida School of Medicine, Gainesville, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida School of Medicine, Gainesville, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.",
"authors": "Camargo|Jose F|JF|http://orcid.org/0000-0001-9584-5011;Simkins|Jacques|J|;Schain|Denise C|DC|;Gonzalez|A Adrian|AA|;Alcaide|Maria L|ML|;Anjan|Shweta|S|;Guerra|Giselle|G|;Roth|David|D|;Kupin|Warren L|WL|;Mattiazzi|Adela|A|;Tan|Yaohong|Y|;Milikowski|Clara|C|;Morris|Michele I|MI|;Abbo|Lilian M|LM|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12836",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCryptococcus\n; donor-derived infection; solid organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D005260:Female; D006801:Humans; D008297:Male; D016377:Organ Transplantation; D014019:Tissue Donors; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12836",
"pmc": null,
"pmid": "29359837",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A cluster of donor-derived Cryptococcus neoformans infection affecting lung, liver, and kidney transplant recipients: Case report and review of literature.",
"title_normalized": "a cluster of donor derived cryptococcus neoformans infection affecting lung liver and kidney transplant recipients case report and review of literature"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-02854",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "Iatrogenic lymphoproliferative disorder (LPD) can develop in patients treated with immunosuppressive drugs for autoimmune or other inflammatory diseases. Here, we report a case of lymphomatoid granulomatosis of the skin that occurred as a methotrexate (MTX)-associated LPD. We also review the relevant literature. A 73-year-old woman presented to our department with an approximately 10-year history of MTX therapy for rheumatoid arthritis. Three months earlier, she noticed a small nodule in her right upper arm. It gradually enlarged, and the center began to decay. Grossly, the lesion was 40 × 40 mm in size with ulceration, and the surrounding skin presented dark red erythema. A biopsy specimen was taken for definitive diagnosis. Histologically, infiltrating growth of medium-to-large atypical lymphocytes was observed underneath the ulceration and was accompanied by small reactive lymphocytes. The atypical lymphocytes demonstrated a tendency to infiltrate the vessels, which showed an angiocentric pattern. Immunohistochemistry revealed that the atypical lymphoid cells were positive for CD79a, CD20, and CD30. In addition, in situ hybridization for Epstein-Barr virus (EBV) revealed expression of EBV-encoded small RNAs. The patient was diagnosed with MTX-associated LPD (lymphomatoid granulomatosis), owing to her history of MTX treatment, the expression of the atypical lymphocytes for B-cell markers and EBV-encoded small RNA, and the angiocentric infiltrating pattern. The lesion reportedly disappeared after withdrawal of MTX.",
"affiliations": "Departments of Diagnostic Pathology, and.;Departments of Diagnostic Pathology, and.;Departments of Diagnostic Pathology, and.;Departments of Diagnostic Pathology, and.;Departments of Diagnostic Pathology, and.;Departments of Diagnostic Pathology, and.;Dermatology, Faculty of Medicine, Oita University, Oita, Japan.;Departments of Diagnostic Pathology, and.",
"authors": "Nishida|Haruto|H|;Oyama|Yuzo|Y|;Kusaba|Takahiro|T|;Kadowaki|Hiroko|H|;Arakane|Motoki|M|;Yokoyama|Shigeo|S|;Hatano|Yutaka|Y|;Daa|Tsutomu|T|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "41(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008230:Lymphomatoid Granulomatosis; D008727:Methotrexate; D012878:Skin Neoplasms",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "448-452",
"pmc": null,
"pmid": "31112139",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Methotrexate-Associated Lymphoproliferative Disorder (Lymphomatoid Granulomatosis) of the Skin.",
"title_normalized": "a case of methotrexate associated lymphoproliferative disorder lymphomatoid granulomatosis of the skin"
} | [
{
"companynumb": "JP-ACCORD-130560",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIMAPROST"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "The first generation protease inhibitors has been the mainstay of hepatitis C treatment for the last couple of years, showing marked improvement in sustained virological response, but also increased side effects. Infection has emerged as a common complication of telaprevir and boceprevir in combination with peginterferon and ribavirin, usually caused by common pathogens. We present the case of a 65 years old man who developed a Mycobacterium abscessus pulmonary infection during treatment with telaprevir, peginterferon and ribavirin. The patient was successfully treated with amikacin, imipenem and chlarithromycin. The present case is relevant for increasing awareness for recognition of opportunistic infections and particularly nontuberculous mycobacterial infections in patients receiving triple therapy for chronic hepatitis C, especially in cirrhotic subjects who develop significant lymphopenia.",
"affiliations": "Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Afiliacja Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Infectious Diseases, School of Medicine, Pontificia Universidad Católica de Chile.;Department of Infectious Diseases, School of Medicine, Pontificia Universidad Católica de Chile.",
"authors": "Soza|Alejandro|A|;Labbé|Pilar|P|;Arrese|Marco|M|;Riquelme|Arnoldo|A|;Barrera|Francisco|F|;Benítez|Carlos|C|;Huete|Alvaro|A|;Balcells|M Elvira|ME|;Labarca|Jaime|J|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C100416:peginterferon alfa-2a",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "14(1)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic; D006801:Humans; D016867:Immunocompromised Host; D016898:Interferon-alpha; D008231:Lymphopenia; D008297:Male; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D009842:Oligopeptides; D018410:Pneumonia, Bacterial; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "132-6",
"pmc": null,
"pmid": "25536652",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mycobacterium abscessus pulmonary infection during hepatitis C treatment with telaprevir, peginterferon and ribavirin.",
"title_normalized": "mycobacterium abscessus pulmonary infection during hepatitis c treatment with telaprevir peginterferon and ribavirin"
} | [
{
"companynumb": "CL-VERTEX PHARMACEUTICALS-2015-000162",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TELAPREVIR"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nLangerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience.\n\n\nMETHODS\nWe describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death.\n\n\nCONCLUSIONS\nLangerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.",
"affiliations": "Department of Hematology and Medical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Gastroenterology, Loyola University Medical Center, Maywood, IL, USA.;Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14th Street, Suite 650B, Miami, FL, 33136, USA. aalencar@med.miami.edu.",
"authors": "Aguirre|Luis E|LE|http://orcid.org/0000-0002-5377-9252;Schwartz|Ingrid|I|;Chapman|Jennifer|J|;Larsen|Marcelo F|MF|;Alencar|Alvaro|A|",
"chemical_list": "D003561:Cytarabine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02460-3",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2460\n10.1186/s13256-020-02460-3\nCase Report\nAdult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report\nhttp://orcid.org/0000-0002-5377-9252Aguirre Luis E. 1 Schwartz Ingrid 2 Chapman Jennifer 3 Larsen Marcelo F. 4 Alencar Alvaro aalencar@med.miami.edu 5 1 grid.468198.a0000 0000 9891 5233Department of Hematology and Medical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL USA \n2 grid.411451.40000 0001 2215 0876Department of Gastroenterology, Loyola University Medical Center, Maywood, IL USA \n3 grid.26790.3a0000 0004 1936 8606Department of Pathology, University of Miami Miller School of Medicine, Miami, FL USA \n4 grid.26790.3a0000 0004 1936 8606Department of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL USA \n5 grid.419791.30000 0000 9902 6374Department of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14th Street, Suite 650B, Miami, FL 33136 USA \n27 9 2020 \n27 9 2020 \n2020 \n14 16921 6 2019 23 7 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nLangerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience.\n\nCase presentation\nWe describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death.\n\nConclusions\nLangerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.\n\nKeywords\nLangerhans cell histiocytosisLangerhans cell sarcomaCytogeneticsAcute myeloid leukemiaColony-stimulating factorLeukemic transformationChemotherapyCentral nervous systemissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nLangerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells with distinctive protein expression (CD1a/langerin/S100) and ultrastructural features (Birbeck granules) with Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) subtypes [1–3]. Historically, LCH has been classified as a unifocal disease, multifocal unisystem disease, or multifocal multisystem disease [2]. LCS is a rare neoplasm exhibiting aggressive features that carries a poor prognosis. We report a case of a patient with a presentation with symptomatic multisystem multifocal LCH disease with early suggestion of leukemic transformation with particular sensitivity to growth factors. In addition to illustrating the refractoriness and poor outcomes of multisystem LCH in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience to raise awareness of this unusual entity and aid in the earlier identification of its potential complications.\n\nCase presentation\nA 42-year-old Caucasian man presented to our hospital with acute onset of fatigue, nausea, vomiting, early satiety, diarrhea, and weight loss 3 months after LCH had been diagnosed on the basis of biopsy of an asymptomatic lesion on the left arm. His physical examination was pertinent for tender hepatosplenomegaly and multiple eczematous papular lesions on the trunk and extremities. His complete blood count (CBC) results and lactate dehydrogenase (LDH) level were normal. Esophagogastroduodenoscopy (EGD) demonstrated herpes esophagitis and Helicobacter pylori gastritis. Biopsies of the duodenum and esophagus showed involvement by LCH with features suggestive of LCS (Fig. 1). The BRAF V600E mutation was not detected. Imaging did not demonstrate any suspicious bone or central nervous system (CNS) involvement. His bone marrow biopsy (BMBx) showed no LCH or acute myeloid leukemia (AML). He was started on intravenous cytarabine 100 mg/m2 daily for 5 days every 4 weeks, which led to improvement but no resolution of his skin lesions or gastrointestinal (GI) symptoms. After four cycles, his therapy was adjusted to every 2 weeks in view of kinetic failure. This adjustment led to clinical improvement, but his LDH level continued to rise, leading to repeat BMBx performed after cycle 8, which showed no evidence of AML.\nFig. 1 Langerhans cell histiocytosis with progression to Langerhans cell sarcoma involving gastric and small intestine mucosa. Endoscopically derived biopsies of gastric and small intestine mucosa showed involvement by Langerhans cell histiocytosis. Pronounced pleomorphism, apoptosis, and mitotic figures were frequent, consistent with progression to Langerhans cell sarcoma (a; H&E stain, 1000× magnification). Neoplastic cells expressed langerin protein (b; 400× magnification), and a subset showed preserved expression of CD1a (c; 400× magnification). Langerhans cells were negative for S100. Ki67-based proliferative rate was estimated at 85% (d; 400× magnification). Although objective distinction between involvement by systemic Langerhans cell histiocytosis and Langerhans cell sarcoma is difficult, the pleomorphic features of the neoplastic cells, aberrant diminished expression of CD1a and S100, and high proliferative rate support designation as Langerhans cell sarcoma. The result of B-RAF testing was negative\n\n\n\nThree weeks later, he presented with acute left hemianopia resulting from an ischemic cerebrovascular accident. Workup demonstrated circulating blasts, spontaneous tumor lysis syndrome, and disseminated intravascular coagulation (DIC). BMBx confirmed acute monoblastic leukemia with a complex karyotype. Next-generation sequencing (NGS) showed no additional mutations. The patient was started on induction 7 + 3 (daunorubicin/cytarabine), which led to transient resolution of skin lesions that quickly worsened by day 15. The lesions appeared as multiple erythematous papules and nodules throughout the back. Histological sections showed heavily epidermotropic and bandlike dermal infiltrates of leukemic cells in the dermis with pseudo-blisters formed by tumor necrosis (Fig. 2a). A subset of tumor cells showed features of Langerhans cells, including reniform nuclei and atypical large and hyperchromic nuclei (Fig. 2b). Immunophenotyping revealed that the tumor cells were positive for langerin, S100, and CD1a with intratumoral heterogeneity and a Ki67 showing a nearly 80% cell proliferation rate (Fig. 2c, d). The tumor cells were also positive for CD56, CD117, and CD123 in a subset of cells. The immunophenotype supported both myelomonoblastic and Langerhans cell differentiation. Marrow cytogenetics detected t(13:14) in all tumor cells and additional structural abnormalities involving chromosomes 1, 8, 9, 10, and Y. In this particular context, the cutaneous lesions were best classified as cutaneous involvement of leukemia. Cytogenetic profiling with NGS showed nonsynonymous mutation p.E69K affecting the PTPN11 gene (SHP2), homozygous loss of CDKN2A at 9p21, and a tumor mutational burden of 26%.\nFig. 2 Punch biopsy of the skin showing superficial epidermal involvement by a hematopoietic neoplasm. Epidermal erosion and ulceration with underlying hematopoietic infiltrate involving epidermis and upper dermis (a; H&E stain, 100× magnification). The hematopoietic neoplasm is poorly differentiated with blastic nuclear features and round to reniform nuclei. Cellular apoptosis is increased. Numerous small reactive lymphoid cells are also present (b; 500× magnification). The majority of the blastic cells express CD1a by immunohistochemistry (c; 500× magnification) and coexpress langerin (d; 500× magnification). The findings are those of acute monoblastic leukemia with Langerhans cell differentiation involving skin\n\n\n\nHe was started on salvage therapy with CLAG-M (cladribine 5 g/m2, cytarabine 2 g/m2, granulocyte colony-stimulating factor (G-CSF), mitoxantrone 10 g/m2), and after the first dose of filgrastim (G-CSF), he developed acute diplopia with leptomeningeal involvement by AML as identified by brain magnetic resonance imaging and lumbar puncture (Fig. 3). Intensive intrathecal therapy with methotrexate (MTX) was initiated twice per week for six cycles. The patient’s skin lesions and neurologic symptoms resolved with restaging consistent with complete remission. However, 1 week later, his skin lesions recurred, followed by recurrence of neurologic deficits that responded poorly to salvage therapy, including high-dose cytarabine, further intrathecal therapy, and CNS radiation. The patient died 1 year after diagnosis of LCH while undergoing treatment with MTX and cytarabine as a bridge to marrow transplant. Table 1 summarizes the cardinal features associated with this case.\nFig. 3 T1-weighted magnetic resonance imaging (MRI) of the brain with contrast enhancement (sagittal view) and cerebrospinal fluid analysis. Leptomeningeal involvement by acute myeloid leukemia demonstrated by brain MRI with contrast (a) with diffuse pachymeningeal thickening and enhancement overlying the bilateral cerebral hemispheres (white arrows) and cerebrospinal fluid showing abnormal hypercellularity due to the presence of monoblasts (b and c; Wright Giemsa stain at 200× and 1000× magnification, respectively)\n\nTable 1 Oncologic history/summary\n\nJanuary 2017: Skin biopsy showed LCH\t\nFebruary 2017: Progressive nausea/diarrhea, weight loss\t\nMarch 2017: EGD - herpes esophagitis, Barrett’s esophagus, Helicobacter pylori gastritis, Langerhans cell sarcoma in stomach/duodenum\n\n Acyclovir full dose, triple therapy (could not tolerate)\n\n\t\nApril 2017: Persistent nausea/emesis, weight loss\n\n EGD: Resolved herpes esophagitis, Barrett’s esophagus, persistent gastritis, Langerhans cell sarcoma in stomach/duodenum\n\n PET/CT: Diffuse uptake in bone marrow, and GI tract\n\n Brain MRI (−)\n\n Bone MRI: Diffuse marrow changes, no bone lesions\n\n Normal CBC, LDH\n\n BMBx (−)\n\n\t\nMay 2017: Cytarabine 100 mg/m2/d × 5 d\t\nJuly 2017: EGD/colonoscopy post C3 - still significant erythema, biopsy (+)\t\nAugust 2017: Improved but persistent symptoms\n\n Skin biopsy - LCH\n\n\t\nSeptember 2017: C6 - switch to every 2 weeks\t\nOctober 2017: BMBx post C7 – No evidence of disease, dyspoiesis likely from chemo, (−) AML FISH and myeloid NGS\t\nNovember 2017: Right posterior cerebral artery [PCA] thrombus s/p TPA\n\n Circulating blasts: BMBx - acute monoblastic leukemia\n\n Karyotype: 45,XY,der(13;14)(q10;q10)\n\n 45,X,der(Y)t(Y;?)(q11.2;?), sl, der(1)t(1;9)(p10;q10), der(8)t(1;8)(q10;p10), del(10)(p11.2)\n\n AML NGS (−), FISH (−)\n\n\t\nNovember 2017: 7 + 3 - D15: Recurrent skin lesions\n\n BMBx - persistent AML\n\n Karyotype: 45,XY,der(13;14)(q10;q10) \n\n Skin lesion: Leukemia cutis with LCH\n\n (+) AML NGS PTPN11 mutation\n\n FISH (+) homozygous del 9p21\n\n\t\nDecember 2017: CLAG-M - diplopia on D1\n\n (+) MRI and LP for CSF involvement\n\n LP with IT chemo 2x/week × 6 - (−) first LP\n\n Recovery marrow - CR\n\n\t\nJanuary 2018: HiDAC 3 g/m2 x C1 + IT\t\nFebruary 2018: Cytarabine 2 g/m2 + cladribine 5 mg/m2 + mitoxantrone 10 mg/m2 + IT\t\nMarch 2018: MTX 5 g/m2 + cytarabine 3 g/m2 as a bridge to transplant due to new skin lesions + IT\t\nAML acute myeloid leukemia, BMBx bone marrow biopsy, CBC complete blood count, C# cycle number, CLAG-M cladribine, cytarabine, granulocyte colony stimulating factor, mitoxantrone, CR complete response, D# day number, EGD esophagogastroduodenoscopy, FISH fluorescent in situ hybridization, GI gastrointestinal, HiDAC high-dose cytarabine, IT intrathecal, LCH Langerhans cell histiocytosis, LDH lactate dehydrogenase, LP lumbar puncture, MRI magnetic resonance imaging, MTX methotrexate, NGS next generation sequencing, PTPN11 Protein tyrosine phosphatase, non-receptor type 11, TPA tissue plasminogen activator\n\n\n\nDiscussion and conclusions\nLCH is a rare entity that results from atypical clonal proliferation of a subset of mononuclear dendritic cells closely resembling Langerhans cells that derive from myeloid progenitor cells. Somatic mutations activating the MAPK (mitogen-activated protein kinase) signaling pathway are commonly observed in LCH, with BRAF V600E mutation identified in over half cases [6, 7]. LCH is mostly described and studied in children [1]. Median age at the time of diagnosis is 1–3 years with an annual incidence of 3-5 cases per million persons per year in children and 1-2 cases per million persons per year in adults [2, 3] LCH is further stratified into single-system disease with unifocal or multifocal involvement or multifocal multisystem disease with or without risk organ (marrow, liver, or spleen) involvement [1–3]. The majority of adults present with multisystem involvement mostly characterized by osteolytic lesions, skin or mucocutaneous involvement, diabetes insipidus, and hepatosplenomegaly. CNS or GI compromise is uncommon [8–10]. Prognosis correlates with extent of disease and degree of organ dysfunction, with more than half presentations with multisystem disease dying of LCH [4, 11]. LCS, reported mainly in adults, is extremely rare. Differentiation from LCH is challenging because immunophenotype is identical and diagnosis is based on overtly malignant pleomorphic appearance [11–15].\n\nTherapy is extrapolated from pediatric studies and single-institution experiences because clinical trials in adults are lacking [16]. Although the commonly used pediatric approach with vinblastine and prednisone is acceptable, single-agent cytarabine or cladribine has been the preferred first-line option, mostly to minimize steroid-induced toxicity and neuropathy [17]. A review of the management of 58 adults with LCH demonstrated significantly higher response with cytarabine than with vinblastine/prednisone, which also presented worse toxicity with 75% grade 3–4 neuropathy [18]. Recurrences in adults are common. Besides the use of other cytotoxic agents such as clofarabine, the BRAF inhibitor vemurafenib has demonstrated excellent, albeit transient, responses in patients with BRAF V600E mutation [19]. The role of consolidation with allogeneic stem cell transplant is unclear. A review of 87 patients with high-risk LCH who underwent allogeneic transplant demonstrated greater than 70% long-term survival with higher relapse rates with reduced-intensity conditioning [12, 20]. A literature review of LCS described dramatic variation in management from chemotherapy to surgery, radiation, or a combination of them. Chemotherapy regimens were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based with mixed results. Survival was overall poor, 58% at 1 year, and outcomes were poorer in disseminated presentations [12].\n\nOur case highlights the refractoriness of LCH in adults. Agents known to have activity in LCH demonstrated suboptimal responses. Attention to specific events during our patient’s presentation highlight important biologic characteristics of LCH. Molecular therapy was not possible, because no targetable mutation was identified. One central finding was the detection of LCS by EGD biopsy. Although our patient presented with symptomatic multisystem disease that required systemic therapy, the LCS component was minute. A more intensive first-line therapy was contemplated but was believed not to be indicated, considering that the presentation was mostly of LCH with a negligible LCS component with normal CBC, LDH, and BMBx. The best response was achieved after an AML induction/salvage regimen (cladribine, cytarabine, and filgrastim with idarubicin [CLAG-Ida]) that was intentionally chosen in view of the described activity of cladribine in LCH [5, 21]. One is left to wonder if our patient’s outcome would have been different had he received intensive induction chemotherapy for what was ultimately a presentation of myeloid sarcoma.\n\nCNS involvement was another critical event. Although our patient had no suggestion of CNS involvement at initial staging, an ischemic cerebrovascular accident believed to be closely related to the DIC was the hallmark of presentation at disease progression/transformation to AML. Nonetheless, the most intriguing aspect of CNS involvement was the acute development of diplopia after the first dose of G-CSF administered as part of CLAG-Ida. The potential relationship between CNS involvement and G-CSF was highlighted during salvage, when the resolved diplopia recurred after a dose of pegfilgrastim. Numerous serum cytokines, including G-CSF, have been associated with the pathogenesis of LCH [22, 23]. The timing between growth factor injection and development of neurologic deficits implies a potential correlation.\n\nThe homozygous loss of CDKN2A at 9p21 was also an interesting finding when analyzing the cytogenetic profile of our patient’s tumor. In contrast to its counterpart of LCH, a recent study demonstrated frequent homozygous loss of CDKN2A/B locus (9p21) and both MAP2K1 and NRAS genes mutations in LCS, which may provide a future basis for potential targeted therapy [24].\n\nIn summary, LCH remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Although therapeutic targets such as BRAF V600E mutations have been identified, therapeutic options remain limited. An intensive AML induction regimen should be strongly considered for LCH presentations with suggestion of an LCS component with cautious use of growth factors and particular attention to CNS involvement. In view of the limited number of effective therapeutic interventions, patients with refractory cases or atypical presentations of LCH and LCH-related disorders should be encouraged to enroll in one of multiple active clinical trials (Table 2).\nTable 2 Active clinical trials recruiting patients with Langerhans cell histiocytosis and related disorders\n\nStudy title (ClinicalTrials.gov identifier)\tInterventions\tStudy design\tLocations\t\nAraC for Newly Diagnosed Adult Langerhans Cell Histiocytosis\n\n(NCT04121819)\n\n\tDrug: Cytarabine\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tPeking Union Medical College Hospital, Beijing, China\t\nStudy of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders\n\n(NCT02425904)\n\n\tDrug: Clofarabine\tAllocation: Nonrandomized\n\nIntervention model: Single- group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tPhoenix Children’s Hospital, Phoenix, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA\n\nChildren’s Hospital of Los Angeles, Los Angeles, CA, USA (and 12 more)\n\n\t\nLCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis\n\n(NCT02205762)\n\n\tDrug: Prednisone\n\nDrug: Vinblastine\n\nDrug: Mercaptopurine (and 6 more)\n\n\tAllocation: Randomized\n\nintervention model: Parallel assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nPhoenix Children’s Hospital, Phoenix, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 28 more)\n\n\t\nThalidomide, Cyclophosphamide and Dexamethasone for Recurrent/Refractory Adult Langerhans Cell Histiocytosis\n\n(NCT04120519)\n\n\tDrug: Thalidomide combined with dexamethasone and cyclophosphamide\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tPeking Union Medical College Hospital, Beijing, China\t\nVinblastine/Prednisone Versus Single Therapy With Cytarabine for Langerhans Cell Histiocytosis (LCH)\n\n(NCT02670707)\n\n\tDrug: Cytarabine\n\nDrug: Vinblastine/prednisone\n\n\tAllocation: Randomized\n\nintervention model: Parallel assignment\n\nmasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tTexas Children’s Hospital, Houston, TX, USA\t\nDenosumab for the Treatment of Adult LCH\n\n(NCT03270020)\n\n\tDrug: Denosumab 70 mg/ml (XGEVA; Amgen, Charlotte, NC, USA)\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\t251 Hellenic Air Force and VA Athens General Hospital, Department of Endocrinology, Attiki, Greece\t\nCobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders\n\n(NCT04079179)\n\n\tDrug: Cobimetinib\tAllocation: Nonrandomized intervention model: Parallel assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tNACHO Consortium, Memphis, TN, USA\n\nTexas Children’s Hospital, Houston, TX, USA\n\n\t\nA Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation\n\n(NCT03585686)\n\n\tDrug: Vemurafenib\n\nDrug: Cytarabine\n\nDrug: 2-Chlorodeoxyadenosine\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tDmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation\t\nInherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)\n\n(NCT04100408)\n\n\tOther: Biospecimen collection\n\nOther: Laboratory biomarker analysis\n\nOther: Questionnaire administration\n\n\tObservational model: Family-based\n\nTime perspective: Prospective\n\n\tBaylor College of Medicine/Dan L. Duncan Comprehensive Cancer Center at Baylor St. Luke’s Medical Center, Houston, TX, USA\t\nA Study of Memory, Thinking, and Brain Imaging in Adults With Histiocytosis\n\n(NCT03127709)\n\n\tBehavioral: Trail Making Test parts A and B\n\nBehavioral: Brief Test of Attention\n\nBehavioral: Symbol Span (and 8 more)\n\n\tObservational model: Cohort\n\nTime perspective: Prospective\n\n\tMemorial Sloan Kettering Basking Ridge, Basking Ridge, NJ, USA\n\nMemorial Sloan Kettering Monmouth, Middletown, NJ, USA\n\nMemorial Sloan Kettering Cancer Center @ Suffolk, Commack, NY, USA (and 1 more)\n\n\t\nTargeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)\n\n(NCT03155620)\n\n\tProcedure: Biopsy\n\nProcedure: Biospecimen collection\n\nDrug: Ensartinib (and 12 more)\n\n\tAllocation: Nonrandomized\n\nIntervention model: Parallel assignment\n\nMasking: None (open label)\n\nPrimary purpose: Screening\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nPhoenix Children’s Hospital, Phoenix, AZ, USA (and 143 more)\n\n\t\nPalbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)\n\n(NCT03526250)\n\n\tOther: Laboratory biomarker analysis\n\nDrug: Palbociclib\n\nOther: Pharmacological study\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nPhoenix Children’s Hospital, Phoenix, AZ, USA (and 93 more)\n\n\t\nUlixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)\n\n(NCT03698994)\n\n\tOther: Pharmacokinetic study\n\nDrug: Ulixertinib\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 94 more)\n\n\t\nOlaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)\n\n(NCT03233204)\n\n\tDrug: Olaparib\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 102 more)\n\n\t\nErdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)\n\n(NCT03210714)\n\n\tDrug: Erdafitinib\n\nOther: Laboratory biomarker analysis\n\nOther: Pharmacological study\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 103 more)\n\n\t\nPI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)\n\n(NCT03213678)\n\n\tOther: Laboratory biomarker analysis\n\nOther: Pharmacological study\n\nDrug: Samotolisib\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 104 more)\n\n\t\nTazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)\n\n(NCT03213665)\n\n\tOther: Laboratory biomarker analysis\n\nDrug: Tazemetostat\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nPhoenix Children’s Hospital, Phoenix, AZ, USA (and 106 more)\n\n\t\nLarotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)\n\n(NCT03213704)\n\n\tDrug: Larotrectinib\n\nDrug: Larotrectinib sulfate\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 105 more)\n\n\t\nCD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation\n\n(NCT01966367)\n\n\tBiological: CD34 stem cell selection therapy\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tNewYork-Presbyterian Morgan Stanley Children’s Hospital, Columbia University, New York, NY, USA\t\nVemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)\n\n(NCT03220035)\n\n\tOther: Laboratory biomarker analysis\n\nDrug: Vemurafenib\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tChildren’s Hospital of Alabama, Birmingham, AL, USA\n\nCardon Children’s Medical Center, Mesa, AZ, USA\n\nArkansas Children’s Hospital, Little Rock, AR, USA (and 103 more)\n\n\t\nAllogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies\n\n(NCT01652092)\n\n\tDrug: Alemtuzumab 0.3 mg\n\nDrug: Cyclophosphamide\n\nDrug: Busulfan (and 6 more)\n\n\tAllocation: Nonrandomized\n\nintervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA\t\nStudy to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations\n\n(NCT02124772)\n\n\tDrug: Trametinib\n\nDrug: Dabrafenib\n\n\tAllocation: Nonrandomized\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tNovartis Investigative Site, Phoenix, AZ, USA\n\nNovartis Investigative Site, San Francisco, CA, USA\n\nNovartis Investigative Site, Baltimore, MD, USA (and 13 more)\n\n\t\nPediatric Long-Term Follow-up and Rollover Study\n\n(NCT03975829)\n\n\tDrug: Dabrafenib\n\nDrug: Trametinib\n\n\tIntervention model: Single-group assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\t\t\nCD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant\n\n(NCT02061800)\n\n\tDevice: CliniMACS CD34+ reagent system (Miltenyi Biotech, Bergisch Gladbach, Germany)\n\nDrug: Thiotepa\n\nDrug: Cyclophosphamide (and 6 more)\n\n\tAllocation: Nonrandomized\n\nIntervention model: Parallel assignment\n\nMasking: None (open label)\n\nPrimary purpose: Treatment\n\n\tColumbia University Medical Center, New York, NY, USA\t\nList is current as of October 25, 2019. Adapted from ClinicalTrials.gov\n\n\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nLEA and IS were involved in data collection, designed the case report protocol, reviewed the existing literature, and drafted the paper. AA and MFL were involved in the care of the patient, designed the treatment protocol, and supervised the data collection. JC analyzed the pathology slides and submitted the figures and footnotes. AA codrafted, reviewed, and approved the final manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nLEA and IS are resident physicians at the Department of Internal Medicine at the University of Miami and Jackson Memorial Hospital. MFL works as assistant professor of gastroenterology and is the medical director of the Gastrointestinal Endoscopy Unit at Jackson Memorial Hospital and at the University of Miami Miller School of Medicine. JC works as associate professor of pathology at the University of Miami. She is the director of the Immunohistochemistry Laboratory and associate program director at the Department of Pathology and Laboratory Medicine at the University of Miami and Jackson Memorial Hospital. AA works as assistant professor of medicine at the University of Miami and is a member of the lymphoma program at the University of Miami Sylvester Comprehensive Cancer Center.\n\nFunding\nThe authors have no sources of funding to declare.\n\nAvailability of data and materials\nThis report does not contain any data. This section is not applicable.\n\nEthics approval and consent to participate\nNo ethics approval was required for the drafting of this report.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Stockschlaeder M Sucker C Adult Langerhans cell histiocytosis Eur J Haematol 2006 76 363 368 10.1111/j.1600-0609.2006.00648.x 16548916 \n2. Broadbent V Egeler RM Nesbit ME Jr Langerhans cell histiocytosis: clinical and epidemiological aspects Br J Cancer Suppl 1994 23 S11 S16 8075001 \n3. Baumgartner I von Hochstetter A Baumert B Langerhans’-cell histiocytosis in adults Med Pediatr Oncol 1997 28 1 9 14 10.1002/(SICI)1096-911X(199701)28:1<9::AID-MPO3>3.0.CO;2-P 8950330 \n4. Lahey ME Histiocytosis-X: an analysis of prognostic factors J Pediatr 1975 87 184 189 10.1016/S0022-3476(75)80576-2 1151558 \n5. Saven A Figueroa ML Piro LD 2-Chlorodeoxyadenosine to treat refractory histiocytosis X N Engl J Med 1993 329 10 734 735 10.1056/NEJM199309023291013 \n6. Badalian-Very G Vergilio JA Degar B Recurrent BRAF mutations in Langerhans cell histiocytosis Blood 2010 116 11 1919 1923 10.1182/blood-2010-04-279083 20519626 \n7. Sahm F Capper D Preusser M BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis Blood 2012 120 12 e28 e34 10.1182/blood-2012-06-429597 22859608 \n8. Arcico M Girschikofsky M Genereau T Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocytic Society Eur J Cancer 2003 39 2341 2348 10.1016/S0959-8049(03)00672-5 14556926 \n9. French Langerhans’ Cell Histiocytosis Study Group A multicentre retrospective survey of Langerhans’ cell histiocytosis: 348 cases observed between 1983 and 1993 Arch Dis Child 1996 75 1 17 24 10.1136/adc.75.1.17 8813865 \n10. Singhi AD Montgomery EA Gastrointestinal tract Langerhans cell histiocytosis: a clinicopathologic study of 12 patients Am J Surg Pathol 2011 35 2 305 310 10.1097/PAS.0b013e31820654e4 21263252 \n11. Zwerdling T Won E Shane L Langerhans cell sarcoma: case report and review of world literature J Pediatr Hematol Oncol 2014 36 6 419 425 10.1097/MPH.0000000000000196 24942035 \n12. Howard JE Dwivedi RC Masterson L Langerhans cell sarcoma: a systematic review Cancer Treat Rev 2015 41 4 320 331 10.1016/j.ctrv.2015.02.011 25805533 \n13. Nakamine H Yamakawa M Yoshino T Langerhans cell histiocytosis and Langerhans cell sarcoma: current understanding and differential diagnosis J Clin Exp Hematop 2016 56 2 109 118 10.3960/jslrt.56.109 27980300 \n14. Ferringer T Banks PM Metcalf JS Langerhans cell sarcoma Am J Dermatopathol 2006 28 36 39 10.1097/01.dad.0000146314.52378.c2 16456323 \n15. Pileri S Grogan TM Harris NL Tumors of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study group based on 61 cases Histopathology 2002 41 1 29 10.1046/j.1365-2559.2002.01418.x 12121233 \n16. Duan MH Han X Li J Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: a single-center retrospective study Leuk Res 2016 42 43 46 10.1016/j.leukres.2016.01.012 26859782 \n17. Girschikofsky M Arico M Castillo D Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net Orphanet J Rare Dis 2013 8 72 10.1186/1750-1172-8-72 23672541 \n18. Cantu MA Lupo PJ Bilgi M Optimal therapy for adults with Langerhans cell histiocytosis bone lesions PLoS One 2012 7 8 e43257 10.1371/journal.pone.0043257 22916233 \n19. Haroche J Cohen-Aubart F Emile JF Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation Blood. 2013 121 9 1495 1500 10.1182/blood-2012-07-446286 23258922 \n20. Veys PA Nanduri V Baker KS Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning Br J Haematol 2015 169 5 711 718 10.1111/bjh.13347 25817915 \n21. Saven A Foon KA Piro LD 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis Ann Intern Med 1994 121 6 430 432 10.7326/0003-4819-121-6-199409150-00006 7914398 \n22. Morimoto A Oh Y Nakamura S Inflammatory serum cytokines and chemokines increase associated with the disease extent in pediatric Langerhans cell histiocytosis Cytokine. 2017 97 73 79 10.1016/j.cyto.2017.05.026 28582647 \n23. Kannourakis G Abbas A The role of cytokines in the pathogenesis of Langerhans cell histiocytosis Br J Cancer Suppl 1994 23 S37 S40 8075004 \n24. Xerri L Adélaïde J Popovici C CDKN2A/B deletion and double-hit mutations of the MAPK pathway underlie the aggressive behavior of Langerhans cell tumors Am J Surg Pathol 2018 42 2 150 159 10.1097/PAS.0000000000000989 29194093\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "14(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute myeloid leukemia; Central nervous system; Chemotherapy; Colony-stimulating factor; Cytogenetics; Langerhans cell histiocytosis; Langerhans cell sarcoma; Leukemic transformation",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D002648:Child; D003561:Cytarabine; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D008297:Male; D011379:Prognosis; D012509:Sarcoma; D012983:Soft Tissue Neoplasms",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "169",
"pmc": null,
"pmid": "32979930",
"pubdate": "2020-09-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8102196;8813865;29194093;28582647;25805533;26859782;23258922;24942035;14556926;25817915;16548916;23672541;12121233;21263252;8950330;7914398;8075001;1151558;22859608;27980300;22916233;8075004;16456323;20519626",
"title": "Adult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report.",
"title_normalized": "adult langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202014079",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nApart from cases related to direct inoculation, pasteurellosis is a rare opportunistic infection occurring in predisposed subjects. Close contact with domestic animals, usually cats, is generally reported. Localized ENT forms are possible and are due to oropharyngeal carriage.\n\n\nMETHODS\nWe present the case of a patient with no notable history, who presented with laryngeal dyspnea and hyperthermia leading to a diagnosis of acute epiglottitis. Bacteremia was detected and blood cultures were positive for Pasteurella multocida. Treatment consisted of the standard treatment for acute epiglottitis with hospitalisation and intravenous antibiotics.\n\n\nCONCLUSIONS\nThis patient presented a history of animal exposure, but no other known risk factors. The activity spectrum of antibiotic therapy for epiglottitis should include H. influenzae and this case illustrates the diversity of the micro-organisms potentially involved. Immunosuppression or another chronic disease does not appear to be a prerequisite for ENT infection.",
"affiliations": "Service d'ORL et CCF, Hôpital Huriez, CHU de Lille, 1 place de Verdun, 59037 Lille cedex, France.;Service d'ORL et CCF, Centre Hospitalier de Boulogne sur Mer, 62321 Boulogne sur Mer, France.;Service d'ORL et CCF, Hôpital Huriez, CHU de Lille, 1 place de Verdun, 59037 Lille cedex, France; INSERM U 908, Université des Sciences et Technologies de Lille, UFR de Biologie - SN3, 59655 Villeneuve d'Ascq, France. Electronic address: francois.mouawad@chru-lille.fr.",
"authors": "Jan|L|L|;Boute|P|P|;Mouawad|F|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.anorl.2020.06.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-7296",
"issue": "138(2)",
"journal": "European annals of otorhinolaryngology, head and neck diseases",
"keywords": "Epiglottitis; Pasteurella multocida; Septicemia; Zoonosis",
"medline_ta": "Eur Ann Otorhinolaryngol Head Neck Dis",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002415:Cats; D004826:Epiglottitis; D006801:Humans; D010326:Pasteurella Infections; D016979:Pasteurella multocida",
"nlm_unique_id": "101531465",
"other_id": null,
"pages": "100-102",
"pmc": null,
"pmid": "32600824",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pasteurella multocida acute epiglottitis.",
"title_normalized": "pasteurella multocida acute epiglottitis"
} | [
{
"companynumb": "FR-DRREDDYS-SPO/FRA/21/0139099",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "In dermato-oncology, interferon-alpha is widely used as treatment of cutaneous lymphoma and as adjuvant therapy in high risk malignant melanoma. With increasingly wide administration of interferon-alpha (IFN-alpha), not only early-onset side effects, such as influenza-like symptoms, but also uncommon late-onset side effects are being recognized. We present three patients with melanoma who developed rare side effects in the course of adjuvant IFN-alpha-therapy: sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy. Based on current knowledge a causal relationship between these diseases and the administration of IFN-alpha can neither be affirmed or absolutely ruled out. Therefore special attention should be paid to such coincidences.",
"affiliations": "Klinik für Dermatologie und Venerologie Otto-von-Guericke-Universität, Magdeburg.",
"authors": "Kreutzer|Katharina|K|;Bonnekoh|Bernd|B|;Franke|Ingolf|I|;Ulrich|Jens|J|;Gollnick|Harald|H|",
"chemical_list": "D016898:Interferon-alpha",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1610-0379",
"issue": "2(8)",
"journal": "Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG",
"keywords": null,
"medline_ta": "J Dtsch Dermatol Ges",
"mesh_terms": "D000368:Aged; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009157:Myasthenia Gravis; D018917:Optic Neuropathy, Ischemic; D012507:Sarcoidosis; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101164708",
"other_id": null,
"pages": "689-94",
"pmc": null,
"pmid": "16279234",
"pubdate": "2004-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy: severe side effects of adjuvant interferon-alpha-therapy in malignant melanoma?.",
"title_normalized": "sarcoidosis myasthenia gravis and anterior ischaemic optic neuropathy severe side effects of adjuvant interferon alpha therapy in malignant melanoma"
} | [
{
"companynumb": "DE-009507513-2003-07-1061",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2B"
},
"drugadditional": "2",... |
{
"abstract": "Peripheral blood hematopoietic stem cell mobilization is widely performed in a variety of clinical facilities and is believed to be a safe outpatient procedure. In this report, we describe a child with neuroblastoma who developed an extremely severe acute lung injury after granulocyte colony-stimulating factor was used for peripheral hematopoietic stem cell mobilization. A 3-year-old boy with a medical history of patent foramen ovale and secundum atrial septal defect was diagnosed with an MYCN-amplified neuroblastoma and treated with chemotherapy. During stem cell mobilization with filgrastim, the boy was in very good clinical condition, with a peripheral white blood cell (WBC) count of 57.17 K/μL, but he suddenly deteriorated, and nausea, seizures, and nystagmus were observed. The patient developed dyspnea with hemoptysis, and lung computed tomography showed bilateral asymmetrical pulmonary opacification demonstrating an anteroposterior density gradient. Because of rapidly progressing circulatory and respiratory failure, the child was hospitalized in the intensive care unit. Corticosteroid therapy, broad-spectrum antibiotic therapy, and cardiovascular support with mechanical ventilation were immediately instituted, and the child recovered without sequelae. The presented case emphasizes that life-threatening complications can occur during granulocyte colony-stimulating factor administration, and patient surveillance is warranted, especially if high leukocyte counts are observed or the patient exhibits cardiopulmonary signs.",
"affiliations": "Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Paediatric Anaesthesiology and Intensive Care, Wroclaw Medical University, Wroclaw, Poland.;Department of General and Interventional Radiology and Neuroradiology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland. Electronic address: ussowicz@tlen.pl.",
"authors": "Miśkiewicz-Migoń|Izabella|I|;Miśkiewicz-Bujna|Justyna|J|;Rosa|Monika|M|;Kubica-Cielińska|Anna|A|;Bladowska|Joanna|J|;Janczar|Szymon|S|;Ussowicz|Marek|M|",
"chemical_list": "D006401:Hematologic Agents; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.06.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D055371:Acute Lung Injury; D002675:Child, Preschool; D000069585:Filgrastim; D006401:Hematologic Agents; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009447:Neuroblastoma",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2849-2853",
"pmc": null,
"pmid": "32713816",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe, Reversible Acute Lung Injury During Autologous Hematopoietic Stem Cell Mobilization After Filgrastim in a Child With Neuroblastoma: A Case Report.",
"title_normalized": "severe reversible acute lung injury during autologous hematopoietic stem cell mobilization after filgrastim in a child with neuroblastoma a case report"
} | [
{
"companynumb": "PL-ACCORD-194918",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Skin lesions are frequently encountered in clinical practice which can be a presentation of systemic diseases not excluding an occult malignancy. Commonly reported paraneoplastic dermatologic manifestations include acanthosis nigricans, dermatomyositis, erythroderma, hypertrophic osteoarthropathy, Sweet syndrome, and paraneoplastic pemphigus (PNP). PNP is a rare autoimmune mucocutaneous disease characterized by severe stomatitis, polymorphic skin eruptions, and associated underlying neoplasms most commonly non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and Castleman disease. PNP is characterized on histopathology as dyskeratotic epithelial cells with acantholysis with a typical immunofluorescence staining pattern of direct and/or indirect staining of intercellular, basement membrane, and dermoepidermal junction with immunoglobulin-G and C3. PNP has been described to have poor prognosis with a mortality range of 75-90% and a mean survival of less than 1year. We describe a previously unreported case of PNP associated with acute myeloid leukemia (AML) where the patient presented with a nonhealing ulcer and hemorrhagic crusting on the face that did not respond to antimicrobials and steroids. Investigations revealed leukocytosis with peripherally circulating blasts. Skin biopsy revealed an evolving PNP and bone marrow biopsy confirmed evidence of AML. The patient underwent induction, consolidation, and then successful allogenic bone marrow transplantation with complete remission. The skin lesion, which was initially refractory to treatments, surprisingly resolved within 7days of starting induction chemotherapy. In this case, the skin lesion was a key factor in early diagnosis and instituting treatment for the underlying AML. Early intervention gave our patient a better outcome with an ongoing survival of 18months since diagnosis, maintaining complete remission.",
"affiliations": "Department of Internal Medicine, West Penn Allegheny Health System, Pittsburgh, PA, USA. Electronic address: medisid@gmail.com.;Department of Internal Medicine, West Penn Allegheny Health System, Pittsburgh, PA, USA.;Department of Internal Medicine, West Penn Allegheny Health System, Pittsburgh, PA, USA.;Department of Pathology, West Penn Allegheny Health System, Pittsburgh, PA, USA.;Department of Hematology and Cellular Therapy, Western Pennsylvania Cancer Institute, Pittsburgh, PA, USA.;Department of Hematology and Cellular Therapy, Western Pennsylvania Cancer Institute, Pittsburgh, PA, USA.",
"authors": "Siddiqui|Salahuddin|S|;Bilal|Mohammad|M|;Otaibi|Zachary|Z|;Bilimoria|Farshaad|F|;Patel|Nihar|N|;Rossetti|James|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.hemonc.2016.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "10(3)",
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Acute myeloid leukemia; Criteria; Paraneoplastic pemphigus; Presentation; Resolution; Skin",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": "D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D010392:Pemphigus",
"nlm_unique_id": "101468532",
"other_id": null,
"pages": "155-160",
"pmc": null,
"pmid": "27352260",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraneoplastic pemphigus as a presentation of acute myeloid leukemia: Early diagnosis and remission.",
"title_normalized": "paraneoplastic pemphigus as a presentation of acute myeloid leukemia early diagnosis and remission"
} | [
{
"companynumb": "US-009507513-1710USA005508",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Laboratory studies have suggested that rapidly alternating chemotherapy and accelerated radiation therapy might act synergistically. We evaluated the toxicity and effectiveness of this approach in muscle infiltrating transitional cell carcinoma of the bladder in patients who were poor risks for or who refused cystectomy. We treated 18 men and 3 women with stage T2 or T3 transitional cell carcinoma of the bladder by transurethral resection, followed by 3 cycles of chemotherapy (during weeks 1, 4 and 7) rapidly alternating with 3 cycles of twice-a-day radiation therapy (during weeks 2, 5 and 8). Chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin. The total dose of radiation therapy was 5,400 to 6,000 cGy, during 6 1/2 weeks and the total duration of chemotherapy and radiation therapy was 7 1/2 weeks. One patient died of hematological toxicity during treatment. With a median followup of 2 years (range 0.5 to 5.5 years) the observed survival rate was 72% at 2 years and 60% at 3 years. To date, only 1 patient (5%) had recurrence of invasive cancer in the pelvis. Only 3 others (15%) had carcinoma in situ but to date none has required cystectomy. Bladder function was normal in 15 of 18 evaluable patients (83.5%). This pilot study suggests that chemotherapy alternating with radiation therapy produced an encouraging survival rate without cystectomy and deserves further study. These patients require continued surveillance for carcinoma in situ.",
"affiliations": "Beth Israel Medical Center, New York, New York.",
"authors": "Vikram|B|B|;Malamud|S|S|;Silverman|P|P|;Hecht|H|H|;Grabstald|H|H|",
"chemical_list": "D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/s0022-5347(17)35027-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-5347",
"issue": "151(3)",
"journal": "The Journal of urology",
"keywords": null,
"medline_ta": "J Urol",
"mesh_terms": "D000206:Actuarial Analysis; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D002945:Cisplatin; D003131:Combined Modality Therapy; D015653:Cystectomy; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009130:Muscle, Smooth; D009367:Neoplasm Staging; D010865:Pilot Projects; D016019:Survival Analysis; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms; D014747:Vinblastine",
"nlm_unique_id": "0376374",
"other_id": null,
"pages": "602-4",
"pmc": null,
"pmid": "8308967",
"pubdate": "1994-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A pilot study of chemotherapy alternating with twice-a-day accelerated radiation therapy as an alternative to cystectomy in muscle infiltrating (stages T2 and T3) cancer of the bladder: preliminary results.",
"title_normalized": "a pilot study of chemotherapy alternating with twice a day accelerated radiation therapy as an alternative to cystectomy in muscle infiltrating stages t2 and t3 cancer of the bladder preliminary results"
} | [
{
"companynumb": "US-PFIZER INC-2021773527",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nDose-dense chemotherapy consisting of a combination of epirubicin and cyclophosphamide (EC) improves the survival of patients with breast cancer. Although pegfilgrastim was used at a subcutaneous dose of 6.0 mg in a pivotal study of dose-dense EC treatment, pegfilgrastim at a dose of 3.6 mg has been approved in Japan. We have assessed the feasibility of dose-dense EC treatment supported with a 3.6 mg dose of pegfilgrastim by evaluating the relative dose intensity (RDI) and safety of the treatment, together with measuring the pegfilgrastim concentrations remaining on the day of starting the next cycle of chemotherapy.\n\n\nMETHODS\nPatients with primary breast cancer received a total of 4 cycles of dose-dense EC treatment every 2 weeks, together with a subcutaneous injection of 3.6 mg pegfilgrastim on the day after chemotherapy. The serum granulocyte colony-stimulating factor (G-CSF) concentrations were measured on the 15th day of every chemotherapy cycle.\n\n\nRESULTS\nFrom March 2015 through to July 2016, a total of 51 patients (median age 51 years; range 33-73 years) were studied. The mean RDI was 95.2% (range 60.0-100%). Although most adverse events were consistent with those reported in previous studies, pneumocystis pneumonia developed in two patients during the following course of docetaxel treatment. The median serum G-CSF concentration was 92.5 (range 30.4-440) pg/ml.\n\n\nCONCLUSIONS\nWith support provided by pegfilgrastim injection at a dose of 3.6 mg, dose-dense EC is feasible and associated with maintenance of a high RDI. There was no clinically significant accumulation of serum G-CSF concentrations associated with the use of a 3.6 mg dose of pegfilgrastim at 2-week intervals.",
"affiliations": "Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan. s-kamei@med.nagoya-u.ac.jp.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Division of Surgical Oncology, Department of Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.;Department of Breast and Endocrine Surgery, Nagoya Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.",
"authors": "Morita|Sachi|S|http://orcid.org/0000-0002-3115-2336;Kikumori|Toyone|T|;Tsunoda|Nobuyuki|N|;Inaishi|Takahiro|T|;Adachi|Yayoi|Y|;Ota|Akiko|A|;Shibata|Masahiro|M|;Matsuoka|Ayumu|A|;Nakanishi|Kenichi|K|;Takeuchi|Dai|D|;Mizutani|Takefumi|T|;Shimokata|Tomoya|T|;Hayashi|Hironori|H|;Maeda|Osamu|O|;Ando|Yuichi|Y|",
"chemical_list": "D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D015251:Epirubicin; D003520:Cyclophosphamide; D000069585:Filgrastim",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-017-1177-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "23(1)",
"journal": "International journal of clinical oncology",
"keywords": "Dose-dense EC; Feasibility study; Japan; Pegfilgrastim; Primary breast cancer",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007564:Japan; D008875:Middle Aged; D011092:Polyethylene Glycols; D011446:Prospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "195-200",
"pmc": null,
"pmid": "28791509",
"pubdate": "2018-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "26306520;12123336;25740286;19395467;25733000;18757263;26420402;12488289;15726101;24919931;20803039",
"title": "Feasibility of dose-dense epirubicin and cyclophosphamide with subcutaneous pegfilgrastim 3.6 mg support: a single-center prospective study in Japan.",
"title_normalized": "feasibility of dose dense epirubicin and cyclophosphamide with subcutaneous pegfilgrastim 3 6 mg support a single center prospective study in japan"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2017133609",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "We had cases in which peripheral neuropathy was augmented after changing from mFOLFOX6, a chemotherapy for colorectal cancer, to FOLFIRI and comparatively examined disease status and trends. There were no shared points with respect to patient characteristics, timing of peripheral neuropathy augmentation, drug dosage, etc. It appeared that the change in chemotherapy itself had an effect on neuropathic symptoms. Regarding the change in chemotherapy, the therapeutic agent was switched from oxaliplatin to irinotecan; the cause was unknown, but some effects of these two drugs were suggested. Future investigation, including the examination of genetic mutations, is necessary.",
"affiliations": "Dept. of Pharmacy, Japanese Red Cross Wakayama Medical Center.",
"authors": "Mashimo|Keiji|K|;Fujiwara|Daichiro|D|;Hoshida|Tadafumi|T|;Morimoto|Naomi|N|;Noda|Akihiro|A|;Takeda|Tomoya|T|;Tsubaki|Masanobu|M|;Nishida|Shozo|S|;Sakaguchi|Katsuhiko|K|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D009944:Organoplatinum Compounds; D010523:Peripheral Nervous System Diseases",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "993-995",
"pmc": null,
"pmid": "32541182",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three Cases of Augmented Chemotherapy-Induced Peripheral Neuropathy after Changing from mFOLFOX6 to FOLFIRI Therapy in Patients with Colorectal Cancer.",
"title_normalized": "three cases of augmented chemotherapy induced peripheral neuropathy after changing from mfolfox6 to folfiri therapy in patients with colorectal cancer"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1815144",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnemia is a complication of therapy for hepatitis C virus (HCV) infection, necessitating dose reductions or therapy abandonment. Administration of an erythropoiesis-stimulating agent (ESA) is a common strategy to manage this complication. Clinical data in other patient populations demonstrate increased rates of cardiovascular events, thrombosis, malignancy, and death among ESA recipients. Event rates in the context of HCV treatment are unknown.\n\n\nMETHODS\nAll recipients of interferon-ribavirin-based HCV therapy at the Ottawa Hospital Viral Hepatitis Clinic from October 2003 through October 2006 were identified. Predictors of ESA use were assessed by regression analysis. Adverse events during and after treatment were evaluated.\n\n\nRESULTS\nA total of 174 courses of HCV therapy were initiated. Predictors of ESA use included older age, lower weight, lower baseline hemoglobin level, and infection with HCV genotype 1 or 4. Targeted hemoglobin levels of >110 g/L were achieved in 88% of ESA recipients. Although not statistically significant, sustained virological responses were obtained in more recipients of ESA (54%) than nonrecipients (45%). In the period after HCV treatment, no myocardial infarctions, deep vein thromboses, or pulmonary embolisms occurred; the frequency of stroke and cancer events were low; and rates of adverse events appeared to be similar between groups.\n\n\nCONCLUSIONS\nESA use is not associated with increased risk of cardiovascular events, malignancy, thrombosis, or death in HCV-infected patients during receipt of HCV therapy or in the period after completion. Given the inherent differences in patient populations, practitioners should exercise caution when extrapolating the results of studies of other diseases to HCV infection. Our efficacy and safety analysis suggests against the withholding of ESAs in the management of anemia induced by HCV treatment.",
"affiliations": "Department of Internal Medicine, University of Ottawa, Canada.",
"authors": "Costiniuk|Cecilia T|CT|;Camacho|Fernando|F|;Cooper|Curtis L|CL|",
"chemical_list": "D000998:Antiviral Agents; D006397:Hematinics; D006454:Hemoglobins; D012254:Ribavirin; D007372:Interferons",
"country": "United States",
"delete": false,
"doi": "10.1086/589243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "47(2)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000740:Anemia; D000998:Antiviral Agents; D002318:Cardiovascular Diseases; D005260:Female; D006397:Hematinics; D006454:Hemoglobins; D006526:Hepatitis C; D006801:Humans; D007372:Interferons; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms; D012189:Retrospective Studies; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "198-202",
"pmc": null,
"pmid": "18532889",
"pubdate": "2008-07-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Erythropoiesis-stimulating agent use for anemia induced by interferon-ribavirin treatment in patients with hepatitis C virus infection is not associated with increased rates of cardiovascular disease, thrombosis, malignancy, or death.",
"title_normalized": "erythropoiesis stimulating agent use for anemia induced by interferon ribavirin treatment in patients with hepatitis c virus infection is not associated with increased rates of cardiovascular disease thrombosis malignancy or death"
} | [
{
"companynumb": "CA-AMGEN-CANSP2019216770",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "A 17-year-old woman presented with acute abdominal pain and vomiting 3 h after she attempted to commit suicide by ingesting 30×500 mg paracetamol tablets. The woman was found to have a raised amylase level, and a CT scan confirmed the diagnosis of acute pancreatitis. According to the Naranjo adverse drug reaction probability scale, it is likely that the pancreatitis was induced by the paracetamol ingestion. A literature search reported 36 cases of pancreatitis following excessive doses of paracetamol, however this possible drug reaction is not widely recognised and not documented in the British National Formulary (BNF) list of possible adverse reactions from paracetamol. Being aware of the possibility that abdominal pain following paracetamol overdose may be a manifestation of pancreatitis can help the early detection and initiation of treatment for pancreatitis.",
"affiliations": "Medway Maritime Hospital, Vascular Surgery, Windmill Road, Gillingham, Kent, ME7 5NY, UK.",
"authors": "Fernandes|Roland|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2009()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22096469",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": "15235508;15233697;851712;21686514;9285154",
"title": "Acute pancreatitis following paracetamol overdose.",
"title_normalized": "acute pancreatitis following paracetamol overdose"
} | [
{
"companynumb": "GB-AUROBINDO-AUR-APL-2020-036888",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "1... |
{
"abstract": "Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.",
"affiliations": "Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan.;Division of Stem Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Thoracic and Cardiovascular Surgery, Faculty of Medicine, Niigata University, Niigata, Japan.;Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan.;Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan.;Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan.;Department of Thoracic and Cardiovascular Surgery, Faculty of Medicine, Niigata University, Niigata, Japan.;Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan.;Division of Stem Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan.",
"authors": "Kawamoto|K|K|;Shibasaki|Y|Y|;Sato|S|S|;Nemoto|H|H|;Takizawa|J|J|;Narita|M|M|;Tsuchida|M|M|;Sone|H|H|;Masuko|M|M|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "bronchoscopy; chemotherapy; invasive tracheal aspergillosis; lung transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001228:Aspergillosis; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D016393:Lymphoma, B-Cell; D008297:Male; D000069283:Rituximab; D014133:Tracheal Diseases",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "872-5",
"pmc": null,
"pmid": "26369902",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation.",
"title_normalized": "fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large b cell lymphoma that developed after lung transplantation"
} | [
{
"companynumb": "JP-WATSON-2016-09609",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Stress-induced cardiomyopathy, also known as 'broken heart syndrome' or Takotsubo cardiomyopathy, is characterized by transient systolic dysfunction of the apical and/or mid segments of the left ventricle, in the absence of significant coronary artery disease. We report the case of a 56-year-old male patient with chronic obstructive pulmonary disease (COPD), with stress-induced cardiomyopathy associated with the use of ipratropium bromide, administered in the context of an acute exacerbation of COPD.",
"affiliations": "Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal. Electronic address: filipamelao@gmail.com.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Radiologia, Centro Hospitalar São João, Porto, Portugal.;Serviço de Cardiologia, Centro Hospitalar São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Portugal.",
"authors": "Melão|Filipa|F|;Nunes|José P L|JP|;Vasconcelos|Mariana|M|;Dias|Paula|P|;Almeida|Pedro B|PB|;Rodrigues|Rui|R|;Pinho|Teresa|T|;Madureira|António|A|;Maciel|Maria J|MJ|",
"chemical_list": "D001993:Bronchodilator Agents; D009241:Ipratropium",
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-2551",
"issue": "33(3)",
"journal": "Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology",
"keywords": "Brometo de ipratrópio; Cardiomiopatia de Takotsubo; Cardiomiopatia de stress; Ipratropium bromide; Stress cardiomyopathy; Takotsubo cardiomyopathy",
"medline_ta": "Rev Port Cardiol",
"mesh_terms": "D001993:Bronchodilator Agents; D006801:Humans; D009241:Ipratropium; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8710716",
"other_id": null,
"pages": "175.e1-4",
"pmc": null,
"pmid": "24680554",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stress-induced cardiomyopathy associated with ipratropium bromide therapy in a patient with chronic obstructive pulmonary disease.",
"title_normalized": "stress induced cardiomyopathy associated with ipratropium bromide therapy in a patient with chronic obstructive pulmonary disease"
} | [
{
"companynumb": "PT-WATSON-2015-15931",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPRATROPIUM BROMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The demand of biologic switching is increasing for different reasons.We aimed to define reasons for switching biologics and possible predictors for switching risk,and to estimate data on drug survival.\n115 patients treated with biologics who switched to a second, third,and/or fourth biologic were eligible for this retrospective study.Patients were divided into 2 groups as switched once,and switched twice or more.Drug survival rates were calculated using the Kaplan-Meier method.\nAll patients switched at least one, 36 patients switched twice, and 9 switched thrice. First-, second-, and third-line biologics were mostly switched due to secondary lack of efficacy for skin disease.Each unit increase in age decreased the risk of having ≥2 switches 4% (p=0.038,OR:0.964,95%CI:0.93-0.998),whereas PsA increased the risk of having ≥2 switches 2.69-fold (p=0.026,OR:2.69,95%CI:1.12-6.44).There was significant difference between biologics in terms of drug survival(p=0.001).Adalimumab had a lower drug survival compared to ustekinumab(p<0.001) and secukinumab(p=0.003) in transition from second-line biologic to third-line biologic.\nSwitching biologics was most commonly due to secondary lack of efficacy for skin disease.Lower ages and the presence of PsA were associated with a higher need for switching in long-term.Ustekinumab and secukinumab are superior to adalimumab in clinical practice in terms of drug survival of second-line biologics.",
"affiliations": "Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.;Department of Dermatology and Venereology, Hacettepe University, School of Medicine, Ankara, Turkey.",
"authors": "Akdogan|Neslihan|N|0000-0002-1137-5399;Dogan|Sibel|S|0000-0002-5383-6886;Bostan|Ecem|E|0000-0002-8296-4836;Gulseren|Duygu|D|;Yalici-Armagan|Basak|B|0000-0001-9745-1331;Elcin|Gonca|G|;Evans|Sibel Ersoy|SE|;Karaduman|Aysen|A|;Atakan|Nilgun|N|0000-0003-3700-514X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/17512433.2021.1979394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1751-2433",
"issue": null,
"journal": "Expert review of clinical pharmacology",
"keywords": "Psoriasis; biologics; drug survival; switching; therapy-systemic",
"medline_ta": "Expert Rev Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101278296",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "34519227",
"pubdate": "2021-09-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Age and psoriatic arthritis are important predictors of biologic agent switch in psoriasis.",
"title_normalized": "age and psoriatic arthritis are important predictors of biologic agent switch in psoriasis"
} | [
{
"companynumb": "TR-JNJFOC-20210955091",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Novel anticoagulants are increasingly utilised in lieu of warfarin to treat non-valvular atrial fibrillation. Their clinical use in other non-FDA approved settings is also increasing. We present a case in which a patient abruptly stopped taking dabigatran due to a small bowel obstruction and shortly thereafter suffered a myocardial infarction complicated by left ventricular thrombosis with fatal embolisation to the superior mesenteric artery. In this context, we discuss the possibility of a rebound phenomenon of hypercoagulability with abrupt cessation of novel anticoagulants.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland, USA.;Department of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland, USA.;Department of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland, USA.;Department of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland, USA.",
"authors": "Weiler|Bethany|B|;Marciniak|Ellen T|ET|;Reed|Robert M|RM|;McCurdy|Michael T|MT|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000792:Angiography; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D017809:Fatal Outcome; D006331:Heart Diseases; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D017538:Mesenteric Artery, Superior; D009203:Myocardial Infarction; D013923:Thromboembolism; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D015091:beta-Alanine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25100807",
"pubdate": "2014-07-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16574031;2989545;24766850;2121029;23151669;12902125;15729076;8922911;22709744;25077110;2307788;23425163;3568301;11158482;22231617;23391196",
"title": "Myocardial infarction complicated by left ventricular thrombus and fatal thromboembolism following abrupt cessation of dabigatran.",
"title_normalized": "myocardial infarction complicated by left ventricular thrombus and fatal thromboembolism following abrupt cessation of dabigatran"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-31540GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "A 47-year-old female with attention-deficit/hyperactivity disorder on prescription Adderall presented to the hospital with worsening dyspnea for the one-month duration. She was admitted to the medical intensive care unit with respiratory failure requiring non-invasive positive pressure ventilation. Cardiac catheterization confirmed the diagnosis of non-cardiogenic pulmonary edema. With the discontinuation of Adderall, use of BiPAP, and aggressive diuresis with loop diuretics, there was evidence of symptomatic, laboratory, and radiological improvement. Her symptoms were attributed to Adderall use as a diagnosis of exclusion. To our knowledge, this paper reports the first case of Adderall-induced non-cardiogenic pulmonary edema leading to respiratory failure. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema, and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems.",
"affiliations": "Cardiology, State University of New York Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA.",
"authors": "Khan|Alisha|A|;Talha|Bilal|B|;Vyas|Vrinda|V|;Khan|Usman|U|;Rao|Suman|S|;Dhamoon|Amit|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16371",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16371\nCardiology\nInternal Medicine\nPulmonology\nRoutine Use of Prescription Adderall Leading to Non-cardiogenic Pulmonary Edema and Respiratory Failure\nMuacevic Alexander\nAdler John R\nKhan Alisha 1\nTalha Bilal 2\nVyas Vrinda 2\nKhan Usman 2\nRao Suman 2\nDhamoon Amit 2\n1 Cardiology, State University of New York Upstate Medical University, Syracuse, USA\n2 Internal Medicine, State University of New York Upstate Medical University, Syracuse, USA\nAlisha Khan khanali@upstate.edu\n13 7 2021\n7 2021\n13 7 e1637113 7 2021\nCopyright © 2021, Khan et al.\n2021\nKhan et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/64143-routine-use-of-prescription-adderall-leading-to-non-cardiogenic-pulmonary-edema-and-respiratory-failure\nA 47-year-old female with attention-deficit/hyperactivity disorder on prescription Adderall presented to the hospital with worsening dyspnea for the one-month duration. She was admitted to the medical intensive care unit with respiratory failure requiring non-invasive positive pressure ventilation. Cardiac catheterization confirmed the diagnosis of non-cardiogenic pulmonary edema. With the discontinuation of Adderall, use of BiPAP, and aggressive diuresis with loop diuretics, there was evidence of symptomatic, laboratory, and radiological improvement. Her symptoms were attributed to Adderall use as a diagnosis of exclusion. To our knowledge, this paper reports the first case of Adderall-induced non-cardiogenic pulmonary edema leading to respiratory failure. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema, and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems.\n\nadderall\nnon-cardiogenic pulmonary edema\nrespiratory failure\nstimulant toxicity\nside-effect of prescription adderall\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nOur case presentation is the first case of Adderall-induced non-cardiogenic pulmonary edema leading to respiratory failure in a human. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems. With the growing use of this medication, rare side effects are gradually coming to light.\n\nCase presentation\n\nWe provided care for a 47-year-old female with a past medical history of attention-deficit/hyperactivity disorder (ADHD), hypertension, and fibromyalgia who presented with worsening shortness of breath and difficulty breathing for the one-month duration. Her shortness of breath had begun suddenly while she was sitting and was not associated with pain. Her home medications included lisinopril 5 mg by mouth daily and Adderall 30 mg by mouth daily, which she had recently started taking again after being off of it for approximately four months. She had not required Adderall during that time as she was not working. She denied the use of illicit drugs and she claimed to have been using Adderall as prescribed by her psychiatrist.\n\nIn the Emergency Department, she was noted to be hypoxemic with blood oxygen saturation (SpO2) level around 50%, tachypneic with a respiratory rate of 49 breaths per minute, and tachycardic with a heart rate of 110 beats per minute. On 15 L O2/min via a non-rebreather mask, she was able to maintain a SpO2 in the low 90s. The initial pro-BNP was 5,486 pg/mL with EKG showing sinus tachycardia. Her urine toxicology resulted positive for amphetamines in the urine.\n\nChest x-ray revealed prominent pulmonary vascular markings with scattered ill-defined opacities and associated interstitial thickening favoring underlying pulmonary edema and small bilateral pleural effusions (Figure 1).\n\nFigure 1 Chest x-ray on admission\n\nCT angiogram of the thorax was negative for a pulmonary embolism; however, it showed bilateral diffuse ground-glass opacities with mild interstitial thickening, cardiomegaly with dilation of the right cardiac chamber, leftward interatrial septal bowing, and mild interventricular septal flattening, concerning for elevated right heart pressures (Figure 2).\n\nFigure 2 Computed tomography angiogram (CT-A) of the thorax on admission\n\nShe was admitted to the medical intensive care unit for acute hypoxemic respiratory failure where she was switched to bilevel positive airway pressure (BiPAP) for persistent respiratory distress. Her BiPAP settings consisted of inspiratory positive airway pressure (IPAP) of 14 cmH2O, expiratory positive airway pressure (EPAP) of 5 cmH2O and a fraction of inspired oxygen (FiO2) of 40%. Cardiology was consulted and a transthoracic echocardiogram was performed. Transthoracic echocardiogram revealed a normal ejection fraction of 55%-60% without diastolic dysfunction, an enlarged right ventricle with normal right ventricular systolic function, an estimated pulmonary arterial pressure of 50.96 mmHg and moderate tricuspid regurgitation.\n\nShe was placed on a furosemide drip, which improved her respiratory distress. Right and left heart catheterization was performed to confirm the pulmonary artery pressure and pulmonary capillary wedge pressure. Interestingly, it showed a normal pulmonary artery pressure of 33/15 mmHg (mean 22 mmHg) and a normal wedge pressure of 10/9 mmHg (mean 8 mmHg), confirming non-cardiogenic pulmonary edema. Of note, right ventricular pressure was 33/6 mmHg (mean 11 mmHg), right atrium pressure was 11/10 mmHg (mean 8 mmHg) and aortic pressure was 110/73 mmHg (mean 91 mmHg). In other words, right heart catheterization demonstrated that her pulmonary edema is unlikely to be from a cardiac etiology. A left heart catheterization revealed insignificant coronary artery disease. The pulmonary service was therefore consulted to aid us in determining the cause of her non-cardiogenic pulmonary edema.\n\nHer extractable nuclear antigen panel resulted negative, other than a mildly elevated rheumatoid factor level of 31 IU/mL, a C-reactive protein level of 282 mg/L, and an erythrocyte sedimentation rate of 88 mm/hr. Infective workup including blood cultures, sputum cultures, white blood cell count, and respiratory viral panel resulted negative. HIV, thyroid function panel, and hepatitis C tests resulted negative. She presented to the hospital several months prior to the first documented case of COVID-19; therefore, she was not tested for it at the time.\n\nAfter excluding all other causes, Adderall was deemed to be the culprit behind our patient’s non-cardiogenic pulmonary edema. We continued to diurese the patient with intravenous furosemide injections. With diuresis, her pro-BNP trended down from 5,486 to 32 pg/mL and the patient improved both clinically and radiographically.\n\nOur patient was discharged home in a stable condition on room air with instructions to discontinue Adderall and to avoid any other stimulants. She was instructed to follow up with her primary care physician and psychiatrist for the management of her ADHD.\n\nDiscussion\n\nAdderall is a central nervous system stimulant containing amphetamines, which are used to manage ADHD. Specifically, Adderall is a 3:1 mixture of d- and l-enantiomers of amphetamine salts [1]. Amphetamines primarily increase the release of dopamine and norepinephrine into the synapse and, secondarily, decrease the reuptake of these neurotransmitters [2]. Norepinephrine-induced alpha-adrenergic stimulation results in vasoconstriction and increased total peripheral resistance [3]. Norepinephrine-induced beta-adrenergic stimulation results in increased heart rate, stroke volume, and blood flow to the skeletal muscles [3]. As a result, Adderall toxicity manifests itself most commonly as tachycardia, tachypnea, hyperactivity, mydriasis, tremors, and hyperthermia.\n\nHere, we report a case of a 47-year-old female with ADHD who presented with worsening dyspnea, which was attributed to Adderall use as a diagnosis of exclusion. With the discontinuation of her medication, use of BiPAP, and aggressive diuresis with loop diuretics, there was evidence of symptomatic, laboratory, and radiological improvement.\n\nUpon review of the literature, there are no human case reports of prescription Adderall-induced non-cardiogenic pulmonary edema. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as ARDS, cardiogenic pulmonary edema, and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems [4,5].\n\nCardiogenic pulmonary edema from stimulant abuse is thought to result from acute and chronic cardiomyopathy, myocardial ischemia, hypertensive crisis, diastolic dysfunction, and arrhythmias [6]. On the other hand, non-cardiogenic pulmonary edema from stimulant abuse is postulated to result from alveolar epithelial and endothelial damage and occasionally sustained seizure activity [6]. However, as aforementioned, our patient strictly denied Adderall abuse and maintained that she was using her medication as prescribed.\n\nCocaine, another stimulant, is a known cause of both cardiogenic and non-cardiogenic pulmonary edema whether used intravenously or inhaled via smoking [4,7,8]. Pulmonary edema has been demonstrated in 77% to 85% of cocaine-related deaths in autopsy series [4,9].\n\nARDS is a clinical entity that requires the presence of non-cardiogenic pulmonary edema for diagnosis. Our patient was unlikely to have ARDS because her symptoms progressed gradually over one month, as opposed to the acute nature of ARDS. According to the Berlin ARDS definition, respiratory distress develops rapidly within one week of a known clinical insult [10].\n\nConclusions\n\nIn conclusion, stimulants such as amphetamines can cause both cardiogenic and non-cardiogenic pulmonary edema. Drug-related lung injury is a rare event and is believed to be idiosyncratic. This lung injury cannot be attributed to the dose or duration of the drug. The diagnosis can become tricky when the patient is only on a prescription stimulant like Adderall and there is no history of illicit stimulant use as in the case presented above, as other causes of acute pulmonary edema need to be excluded first.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Amphetamine enantiomer excretion profile following administration of Adderall J Anal Toxicol Cody JT Valtier S Nelson SL 485 492 27 2003 14607004\n2 CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs Trends Pharmacol Sci McMillen BA 429 432 4 1983\n3 Adderall® (amphetamine-dextroamphetamine) toxicity Top Companion Anim Med Fitzgerald KT Bronstein AC 2 7 28 2013 23796480\n4 Pulmonary complications from cocaine and cocaine-based substances: imaging manifestations Radiographics Restrepo CS Carrillo JA Martínez S Ojeda P Rivera AL Hatta A 941 956 27 2007 17620460\n5 The acute respiratory distress syndrome Proc (Bayl Univ Med Cent) Modrykamien AM Gupta P 163 171 28 2015 25829644\n6 Stimulants and the lung: review of literature Clin Rev Allergy Immunol Tseng W Sutter ME Albertson TE 82 100 46 2014 23760760\n7 Fatal pulmonary edema following intravenous “freebase” cocaine use Ann Emerg Med Allred RJ Ewer S 441 442 10 1981 7258760\n8 Pulmonary edema after freebase cocaine smoking--not due to an adulterant Chest Kline JN Hirasuna JD 1009 1010 97 1990 2323234\n9 Pulmonary histopathology in cocaine abusers Hum Pathol Bailey ME Fraire AE Greenberg SD Barnard J Cagle PT 203 207 25 1994 8119721\n10 The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material Intensive Care Med Ferguson ND Fan E Camporota L 1573 1582 38 2012 22926653\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "adderall; non-cardiogenic pulmonary edema; respiratory failure; side-effect of prescription adderall; stimulant toxicity",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16371",
"pmc": null,
"pmid": "34395145",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "7258760;14607004;17620460;22926653;2323234;25829644;8119721;23760760;23796480",
"title": "Routine Use of Prescription Adderall Leading to Non-cardiogenic Pulmonary Edema and Respiratory Failure.",
"title_normalized": "routine use of prescription adderall leading to non cardiogenic pulmonary edema and respiratory failure"
} | [
{
"companynumb": "US-TAKEDA-2021TUS052975",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMPHETAMINE ASPARTATE\\AMPHETAMINE SULFATE\\DEXTROAMPHETAMINE SACCH... |
{
"abstract": "OBJECTIVE\nHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been considered the standard of treatment care for patients with multiple myeloma (MM). Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. This is resulting in a lacking opportunity of cure in patients with MM. The aim of this study was to evaluate the factors which influence mobilization failure in patients with MM.\n\n\nMETHODS\nThis study has been performed in a retrospective manner. Two hundred and thirty-four patients with diagnosed MM who underwent stem cell mobilization after induction chemotherapy at Hacettepe University Hospital between the years of 2003 and 2018 were evaluated.\n\n\nRESULTS\nA total of 234 patients were included in this study. The median age was 54 (32-76) years at the time of diagnosis. In 209 of 234 patients (89.3%) first mobilization trial was successful. At univariate analysis, among parameters identifiable before mobilization, male gender (p = 0.03), number of chemotherapy cycle before stem cell mobilization (p < 0.001), second ASCT (p < 0.001) and immunomodulatory treatment before stem cell mobilization (p < 0.001) predicted mobilization failure. At multivariate analysis, number of chemotherapy cycle before stem cell mobilization (p = 0.03), second ASCT (p < 0.001) and immunomodulatory treatment before stem cell mobilization (p = 0.02) retained independent predictive power.\n\n\nCONCLUSIONS\nDetectable different clinical characteristics of MM patients before initiating mobilization may be predictors of poor mobilization. Therefore, the mobilization protocol should be evaluated on a patient basis. Minimization of exposure to chemotheraputic agents in MM patients, especially immunomodulatory agents, may increase CD34+ cell harvest yields.",
"affiliations": "Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey. Electronic address: hgoker1@gmail.com.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Ondokuz Mayis University, Dept of Hematology, Samsun, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.;Hacettepe University, School of Medicine, Department of Hematology, Ankara, Turkey.",
"authors": "Goker|Hakan|H|;Ciftciler|Rafiye|R|;Demiroglu|Haluk|H|;Turgut|Mehmet|M|;Sayınalp|Nilgun|N|;Haznedaroglu|I C|IC|;Okay|Mufide|M|;Tekin|Fatma|F|;Buyukasık|Yahya|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2019.06.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "59(1)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Mobilization failure; Multiple myeloma; Stem cell mobilization",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012189:Retrospective Studies",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "102595",
"pmc": null,
"pmid": "31492570",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predictive factors for stem cell mobilization failure in multiple myeloma patients: A single center experience.",
"title_normalized": "predictive factors for stem cell mobilization failure in multiple myeloma patients a single center experience"
} | [
{
"companynumb": "TR-AMGEN-TURSP2020145507",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nEffective therapies for hepatocellular carcinoma (HCC) are limited. Molecular profiling of HCC was performed to identify novel therapeutic targets.\n\n\nMETHODS\n350 HCC samples were evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing, amplification, and protein expression.\n\n\nRESULTS\nEGFR, TOPO1, PD-1, TOP2A, SPARC, and c-Met were overexpressed in 25-83% of samples. Decreased expression of RRM1,TS, PTEN, and MGMT occurred in 31-82% of samples. TP53 was mutated in 30%, CTNNB1 in 20%, and BRCA2 in 18%; other gene mutation rates were <5%. TP53-mutated tumors showed significantly higher TOPO2A (90% vs. 38%, P < 0.0001) and TS (56% vs. 29%, P = 0.0139) expression. CTNNB1-mutated tumors had significantly higher AR (56% vs. 21%, P = 0.0017), SPARC (61% vs. 29%, P = 0.0135), PDL1 (29% vs. 0%, P = 0.0256) expression, and BRCA2 mutations (50% vs. 6%, P = 0.0458). Metastases exhibited significantly higher infiltration by PD-1+ lymphocytes (79% vs. 50%, P = 0.047) and TS (31% vs. 14%, P < 0.0003) than primary HCC.\n\n\nCONCLUSIONS\nMultiplatform profiling reveals molecular heterogeneity in HCC and identifies potential therapies including tyrosine kinase, PI3 kinase, or PARP inhibitors for molecular subtypes. Chemotherapy may benefit some tumors. CTNNB1-mutated tumors may respond to multi-target inhibition. These limited and preliminary data require clinical validation.",
"affiliations": "Department of Medicine, Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.;Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Department of Medicine, Hematology/Oncology, Georgetown University Medical Center, Washington, DC.;Caris Life Sciences, Phoenix, Arizona.;Caris Life Sciences, Phoenix, Arizona.;Caris Life Sciences, Phoenix, Arizona.;Caris Life Sciences, Phoenix, Arizona.;Department of Medicine, Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.;Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Ang|Celina|C|;Miura|John T|JT|;Gamblin|T Clark|TC|;He|Ruth|R|;Xiu|Joanne|J|;Millis|Sherri Z|SZ|;Gatalica|Zoran|Z|;Reddy|Sandeep K|SK|;Yee|Nelson S|NS|;Abou-Alfa|Ghassan K|GK|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1002/jso.24086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4790",
"issue": "113(1)",
"journal": "Journal of surgical oncology",
"keywords": "hepatocellular carcinoma; multiplatform molecular profiling; targeted therapy",
"medline_ta": "J Surg Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular; D000069347:Erlotinib Hydrochloride; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009536:Niacinamide; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011505:Protein-Tyrosine Kinases; D012189:Retrospective Studies; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin",
"nlm_unique_id": "0222643",
"other_id": null,
"pages": "55-61",
"pmc": null,
"pmid": "26661118",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comprehensive multiplatform biomarker analysis of 350 hepatocellular carcinomas identifies potential novel therapeutic options.",
"title_normalized": "comprehensive multiplatform biomarker analysis of 350 hepatocellular carcinomas identifies potential novel therapeutic options"
} | [
{
"companynumb": "US-BAYER-2016-035173",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo describe a case of Coccidioides endophthalmitis that resulted in a favorable visual outcome after a combined medical and surgical approach.\n\n\nMETHODS\nA 33-year-old previously healthy woman was referred for evaluation of dyspnea and left-sided vision loss, which began 3 months before, after a trip to Nevada. She was found to have a pulmonary cavitary lesion and fluffy white material in the anterior chamber. An aqueous and vitreous paracentesis grew Coccidioides species. She was managed medically with a total of 7 weekly intravitreal injections of amphotericin B and intravenous liposomal amphotericin B followed by transition to oral posaconazole. Seven months after presentation, to ensure ocular sterilization and to clear the visual axis, she underwent temporary keratoprosthesis implantation, anterior segment reconstruction, removal of a cyclitic membrane and the crystalline lens, pars plana vitrectomy, placement of a pars plana Ahmed drainage device, and penetrating keratoplasty.\n\n\nRESULTS\nAfter surgical intervention and with maintenance posaconazole therapy, the patient had resolution of her dyspnea and improved uncorrected (aphakic) vision with a clear corneal graft, quiet anterior chamber, and normal optic nerve and retina.\n\n\nCONCLUSIONS\nA combined medical and surgical approach resulted in a favorable visual outcome and avoided the need for enucleation.",
"affiliations": "*Department of Ophthalmology and Vision Science, University of California Davis Medical Center, Sacramento, CA; †Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, CA; and ‡Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA.",
"authors": "Ling|Jennifer J|JJ|;Bays|Derek J|DJ|;Thompson|George R|GR|;Moshiri|Ala|A|;Mannis|Mark J|MJ|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C068538:liposomal amphotericin B; C101425:posaconazole; D000666:Amphotericin B",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "36(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D001082:Aqueous Humor; D003045:Coccidioides; D003047:Coccidioidomycosis; D003131:Combined Modality Therapy; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D013508:Ophthalmologic Surgical Procedures; D016896:Treatment Outcome; D014230:Triazoles; D014822:Vitreous Body",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1423-1425",
"pmc": null,
"pmid": "28872517",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Favorable Outcome in Coccidioides Endophthalmitis-A Combined Medical and Surgical Treatment Approach.",
"title_normalized": "favorable outcome in coccidioides endophthalmitis a combined medical and surgical treatment approach"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0094979",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3"... |
{
"abstract": "For patients with Hodgkin Lymphoma (HL) who experience relapse post allogeneic stem cell transplantation, limited treatment options exist, and the ultimate outcome is poor. Recently, the programmed cell death protein-1 (PD-1) inhibitors have shown remarkable efficacy in patients with refractory/relapsed HL, also demonstrating an acceptable safety profile. However, due to effects on T-cell activity, the use of PD-1 inhibitors post allografting may potentially increase the risk of treatment-emergent graft versus host disease. We herein report the clinical course of a patient who experienced multiple relapses of HL post allogeneic stem cell transplantation. He failed several treatment modalities but he responded to escalating doses of the PD-1 inhibitor nivolumab, given at two different treatment time points, also demonstrating minimal and easily manageable toxicity.",
"affiliations": "Departments of Adult Hematology and Stem Cell Transplantation.;Departments of Adult Hematology and Stem Cell Transplantation.;Departments of Medical Imaging, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Departments of Adult Hematology and Stem Cell Transplantation.;Departments of Adult Hematology and Stem Cell Transplantation.",
"authors": "Kaloyannidis|Panayotis|P|;Al Shaibani|Eshrak|E|;Moinnudin|Asif|A|;Al Anezi|Khalid|K|;Al Hashmi|Hani|H|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2021.8780",
"fulltext": "\n==== Front\nHematol Rep\nHR\nHematology Reports\n2038-8322\n2038-8330\nPAGEPress Publications, Pavia, Italy\n\n10.4081/hr.2021.8780\nCase Report\nRepeated courses of escalating doses of Nivolumab in refractory Hodgkin lymphoma with recurrent relapses post allografting: A safe and effective treatment approach\nKaloyannidis Panayotis 1\nAl Shaibani Eshrak 1\nMoinnudin Asif 2\nAl Anezi Khalid 1\nAl Hashmi Hani 1\n1 Departments of Adult Hematology and Stem Cell Transplantation\n2 Departments of Medical Imaging, King Fahad Specialist Hospital, Dammam, Saudi Arabia\nAdult Hematology & Stem Cell Transplantation Department, King Fahad Specialist Hospital, Ammar Bin Thabit St, Al Muraikabat, 314444, Dammam, Saudi Arabia. +966503301174 - +966138442222. pkaloyannidis@yahoo.gr, kalogiannidi. panagiotis@kfsh.sa\nContributions: PK, conception and design of the work; analysis and interpretation of data; writing and revising the manuscript approved the version to be published. ES, contributed to the design of the work and data acquisition. AM, contributed to the data acquisition. KA, HH, AM, ES, PK, critically reviewed the manuscript for important intellectual content and approved the version to be published, accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nConflict of interest: The authors declare no potential conflict of interest.\n\nEthics approval: It has been received. Consent to publication: It has been received. Availability of data and materials: Available by authors.\n\n05 3 2021\n05 3 2021\n13 1 878006 7 2020\n01 2 2021\n©Copyright: the Author(s)\n2021\nLicensee PAGEPress, Italy\nThis work is licensed under a Creative Commons Attribution NonCommercial 4.0 License (CC BY-NC 4.0).\nFor patients with Hodgkin Lymphoma (HL) who experience relapse post allogeneic stem cell transplantation, limited treatment options exist, and the ultimate outcome is poor. Recently, the programmed cell death protein-1 (PD-1) inhibitors have shown remarkable efficacy in patients with refractory/relapsed HL, also demonstrating an acceptable safety profile. However, due to effects on T-cell activity, the use of PD-1 inhibitors post allografting may potentially increase the risk of treatment-emergent graft versus host disease. We herein report the clinical course of a patient who experienced multiple relapses of HL post allogeneic stem cell transplantation. He failed several treatment modalities but he responded to escalating doses of the PD-1 inhibitor nivolumab, given at two different treatment time points, also demonstrating minimal and easily manageable toxicity.\n\nKey words\n\nallogeneic hematopoietic stem cell transplantation\nHodgkin lymphoma\nprogrammed death-1 (PD-1) inhibitors\nFunding: None.\n==== Body\nIntroduction\n\nIn patients allografted for refractory Hodgkin Lymphoma (HL) who experience disease recurrence post allogeneic hematopoietic stem cell transplantation (alloSCT), the traditional immunomodulatory approaches [reduction or discontinuation of immunosuppressive treatment (IST) with or without donor’s lymphocytes infusions (DLIs)] are only partially effective and are usually accompanied with high incidence of induced graft-versus-host disease (GvHD), while chemotherapeutic approaches are mostly unsuccessful.1,2 It has been shown that HL cells have a unique biologic dependence on the programmed cell death protein-1 (PD-1), which is expressed on activated T-cells, and other lymphoid and myeloid cells.3,4 Nivolumab (Opdivo®, Bristol-Meyers Squibb), a fully humanized IgG4 anti–PD-1 monoclonal antibody, has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adults with relapsed/refractory classical Hodgkin Lymphoma (cHL) after autoHSCT and Brentuximab Vendotin (BV) treatment.5,6\n\nFor patients who have relapsed HL post allograft, the inhibition of the PD-1 pathway, might theoretically enhance the graft versus HL (GvHL) effect by upregulating the activation of donor-derived T-cells however, the increased alloreactivity of donor Tcells may also promote severe treatmentemergent GvHD (te-GvHD), thus contributing to increased risk for morbidity and mortality. 7\n\nHerein, we describe the clinical course of a patient with HL, who experienced early relapse post alloSCT and failed to achieve disease control after immunomodulatory approaches (including anti-CD30 infusion), but responded twice to Nivolumab treatment. To reduce the risk of GvHD without negatively affecting the GvHL effect, we treated the patient with escalating doses of Nivolumab.\n\nCase Report\n\nA young male patient, diagnosed at the age of 11 years with nodular sclerosis cHL and stage IIIBS, was initially treated in a pediatric center with the ABVD/COPP regimen. After 6 cycles of treatment he failed to achieve remission and therefore a Bortezomib–based salvage regimen was given, followed by autoSCT after BEAM conditioning regimen (Table 1). Nine months post autoSCT, he experienced disease progression with liver, marrow and multiple sites of lymph node involvement and he subsequently received BV (Table 1). Although there was an initial partial response, eventually, 8 months later, the disease progressed again, and the combination of BV with Bendamustine (BvB) was given as previously described by La Casce et al.8 After 3 cycles of the BvB combination, the disease was assessed to be in very good partial remission (VGPR) and since he had a suitable fully matched sibling donor, he proceeded to alloSCT after a reduced-intensity conditioning regimen, consisting of thiotepa, fludarabine and cyclophosphamide (Table 1). Cyclosporine plus mycophenolate mofetil were administered as GvHD prophylaxis. He engrafted successfully and experienced no GvHD during the early post-transplant period. Three months later, the disease progressed (first relapse post alloSCT), and in addition to IST discontinuation, BV at standard doses was given. With this treatment modality, partial disease control was achieved. However, the patient developed induced GvHD. Steroids plus cyclosporine were initiated, but the GvHD proved to be steroiddependent, therefore the patient continued on steroid-based treatment. Four months later (16 months post allografting), while he was on double IST, he complained of cough and fever. High resolution computed tomography (HRCT) along with lung biopsy confirmed second disease progression post alloSCT (Figure 1A). IST was tapered and Nivolumab was chosen as the next treatment option, since the patient fulfilled the criteria for Nivolumab initiation as per FDA approved indications.5,6 PD-1 expression was not evaluated on the tissue biopsy because this test was not available in our center at that time. Although the standard dose for Nivolumab in adult patients is 240 mg every two weeks, because our patient was a young adolescent and underweight (42 kg), we chose to treat him with at the dose of 3 mg/kg every two weeks in order to minimize treatment-related toxicity and risk of te-GvHD.9 After 2 cycles, significant clinical improvement was noticed. However, the patient complained of severe abdominal pain and diarrhea. Colonic biopsies confirmed te‑GvHD; no other organ involvement. The IST doses were increased while Nivolumab dose was reduced to 2 mg/kg every 3 weeks. After two additional cycles at the aforementioned dose, significant disease improvement according to CT criteria was documented (Figure 1B), and the patient became completely asymptomatic from the respiratory and gastrointestinal systems. At this time point, patient’s family asked for a second opinion from another center. Following the new medical advice, nivolumab treatment was held and the patient continued only IST to control the residual GvHD. Six months after Nivolumab discontinuation, he presented to our center with the third relapse post alloSCT (Figure 2A). He was re-treated with Nivolumab, and in order to avoid severe toxicities and to minimize the risk of severe te-GvHD, we used escalating doses of Nivolumab, starting from 1.5 mg/kg every 2 weeks, with a planned dose increase of 0.5 mg/kg every 2 cycles, if the previous dose was well tolerated. After 8 cycles he achieved a complete metabolic response (mCR) according to PET/CT criteria (Figure 2B). He continued on escalating doses of Nivolumab and since no treatmentrelated toxicity was noticed, he finally was able to receive the maximum dose of 3 mg/kg. He was also on low dose IST (tacrolimus 1 mg daily and prednisone 10 mg every other day) to minimize the risk of the te-GvHD. After the 15th infusion of the treatment, he developed diarrhea. New colon biopsies revealed non-specific colitis changes, and the symptoms attributed to the well-described adverse reaction of the check-point inhibitors.10 Since the patient was in a prolonged remission (7 months after the second course of treatment with PD-1 inhibitor), the decision was to discontinue the Nivolumab infusions and to continue only with low doses of IST treatment of GvHD. After eight months post Nivolumab discontinuation, the patient was evaluated to be in continued mCR with full (100%) donor-derived hematopoietic chimerism.\n\nDiscussion\n\nDespite the well-described GvHL effect, relapse post alloSCT is a major cause for treatment failure, resulting in low likelihood of cure.1,2 The mechanism of evasion from donor-derived T-cell surveillance by malignant cells has not been elucidated yet. It has been reported that T-cells from some alloSCT demonstrate an exhausted T cell phenotype, having also a low capacity to produce cytokines necessary for T-cell cytotoxic activity.11-13 The well-documented overexpression of PD-1 molecules on circulating lymphocytes and HL cells at the time of relapse, suggests that alterations in signaling across the PD1-synapse could be at least an additional pathway for the post alloSCT immune evasion.11 Based on this knowledge, the PD-1/PDL-1 pathway inhibitors could be an effective alternative treatment for HL patients who experience relapse after alloSCT.\n\nFigure 1. HRCT during the first course of Nivolumab treatment. A) Before Nivolumab administration HRCT showed multiple nodules in the lungs bilaterally. The CT guided biopsy confirmed relapse of cHL. B) After the first 4 cycles of Nivolumab administration the HRCT showed excellent response since the majority of the malignant nodules have been disappeared. HRCT: High resolution computed tomography, cHL: classical Hodgkin Lymphoma.\n\nTable 1. Summary of treatment.\n\nRegimen\tDrugs and dosage\tCourses\tResponse\t\nABVD/COPP\tDoxorubicin: 25 mg/m2 for 2 days (1&15)\t6\tInduction failure\t\n\tBleomycin: 10 mg/m2 for 2 days (1&15)\t\t\t\n\tVinblastine: 6 mg/m2 for 2 days (1&15)\t\t\t\n\tDacarbazine: 400 mg/m2 for 2 days (1&15)\t\t\t\n\tCyclophosphamide: 200 mg/m2 for 2 days (1&8)\t\t\t\n\tVincristine: 1.5 mg/m2 for 2 days (1&8)\t\t\t\n\tProcarbazine: 100 mg/m2 for 10 days\t\t\t\n\tPrednisone: 1 mg/kg for 10 days\t\t\t\nAHOD0521\tIfosfamide: 3000 mg/m2 for 4 days (1-4)\t2\tVery good partial response\t\n\tVinorelbine: 25 mg/m2 for 2 days (1&5)\t\t\t\n\tBortezomib: 1.2 mg/m2 for 3 days (1, 4 &8)\t\t\t\nBEAM\tCarmustin (BCNU): 300 mg/m2 for 1 day (D-6)\t\t\t\n\tEtoposide: 100 mg/m2 for 4 days (D-5 to -2)\t\t\t\n\tCytarabine: 200 mg/m2 for4 days (D-5 to -2)\t\t\t\n\tMelphalan: 160 mg/m2 for 1 days (D-1)\t1\tDisease progression: 9 months post autoSCT\t\nBv\tBrentuximab vedotin: 1.8 mg/m2 for 1 day\t8\tDisease progression\t\nBvB\tBrentuximab: 1.8 mg/m2 for 1 day\t3\tVery good partial response\t\n\tBendamustin: 90 mg/m2 for 2 days\t\t\t\nThiotepa, fludarabine and cyclophosphamide\tThiotepa: 7 mg/m2 for 1 day (D-7),\t\t\t\n\tFludarabine: 30 mg/m2 for 3 days (D-5 to -3)\t\t\t\n\tCyclophosphamide: 50 mg/m2 for 2 days (D-5 & -4)\t1\tDisease progression: 3 months post alloSCT\t\n\nOur patient had disease refractory to multiple treatment approaches including autoSCT, alloSCT and antiCD30 monoclonal antibody administration; he eventually achieved mCR after Nivolumab treatment. Timmerman et al. reported the results of Nivolumab treatment in patients with HL who had previously treated with Brentuximab after autoSCT failure. After a median follow-up of 15.4 months (minimum 12 months), the overall response rate (ORR) was 68%, the CR incidence was 8%, while the 1-year progression-free and overall survival were 54% and 94%, respectively. 14 The experience of Nivolumab for relapsed disease post alloSCT is limited and based on small series of patients or case reports. Two retrospective studies reported promising results with ORR of 80% and 95% and high rates of durable complete remissions 42% and 50%.15-17 It is noteworthy that the published ORR for patients who received PD-1 inhibitors for relapsed HL post alloSCT are higher as compared to the response rates that have been observed in patients who were treated with PD-1 inhibitors for disease recurrence post autoSCT or conventional chemotherapy. A plausible explanation for this efficacy inferiority in the autoSCT/conventional chemotherapy setting, could be that the PD- 1 inhibitor acts on patient T-cells and therefore, either intrinsic patient’s lymphocytes deficiency or the previous exposure to chemotherapy, adversely affect the immune response despite priming by PD-1 inhibitor. Oppositely, in the allograft setting, the PD- 1 inhibitor acts on healthy donor-derived Tcells which are also naïve to chemotherapy.\n\nA major complication of Nivolumab administration after alloSCT, apart from the other common side effects, is the increased donor-derived T-cell alloreactivity, thus resulting in te-GvHD.10,15-18 Our patient, after the first 2 cycles of Nivolumab at the dose of 3 mg/kg, developed severe gut te- GvHD which was effectively controlled with IST treatment plus Nivolumab dose reduction. It is worth mentioning that prior to Nivolumab treatment, the patient had already experienced induced-GvHD which is a well-known predisposing factor for GvHD flare after PD-1 inhibitor treatment. 18 So far, there are no definite guidelines regarding the dosing and the duration of treatment with PD-1 inhibitors post allograft. In a prospective phase I/Ib multicenter study, 8 patients were treated with Nivolumab after allograft for relapsed HL (6 patients at 1 mg/kg and 2 patients at 0.5 mg/kg). In the 1 mg/kg cohort there were 2 non-relapse related deaths while 2 patients experienced severe chronic GVHD. On the contrary, no significant toxicities have been observed in the 0.5 mg/kg cohort of patients.19 Onizuca et al. published the clinical course of a patient who received Nivolumab at escalating doses for relapsed HL post alloSCT, starting from 0.5 mg/kg. The dose-escalating ratio was 100% every 4 cycles, with the maximum reached dose of 2 mg/kg; finally, due to te-GvHD occurrence, the dose was reduced to 1 mg/kg. In terms of the primary disease response, the authors reported that only VGPR was achieved.20 In a recent report, Herbaux et al. recommend initiating Nivolumab at a low dose (0.5 mg/kg) followed by escalating doses if no te-GvHD occurs.21 In our case, during the second course of nivolumab treatment, we chose to start with a higher dose (1,5 mg/kg), followed by a lower escalating ratio (0.5 mg/kg every 2-3 cycles) if the medication was well tolerated. By using this treatment schedule, the patient was able to receive in total 15 cycles and after the 7th cycle/infusion he reached the maximum Nivolumab dose of 3 mg/kg without any major complication. Interestingly, the efficacy of Nivolumab was robust even at the lower doses, as our patient, during the second escalating Nivolumab course, achieved mCR after the 7th infusion (ranges of the given doses 1.5-2 mg/kg).\n\nIt has not been reported in the literature whether previous exposure to Nivolumab adversely affects its efficacy or exacerbates toxicity in the case of subsequent administration. Our patient received two nivolumab courses with an interval period of 6 months, and both times he responded successfully, suggesting that at least in certain cases, Nivolumab re-administration retains its efficacy even if malignant cells have been previously exposed to it.\n\nFigure 2. PET/CT scan during the second course of Nivolumab administration. A) Six months after Nivolumab discontinuation the PET/CT showed disease recurrence in the lungs, axillary and retroperitoneal lymph nodes. B) After 8 cycles of Nivolumab readministration, mCR was documented according to PET/CT criteria. PET/CT: Positron emission tomography/computed tomography, mCR: metabolic complete remission.\n\nConclusions\n\nIn this heavily pretreated patient with refractory disease, Nivolumab, given at intermediate dose followed by low rate of dose escalation, was a well-tolerated treatment, offering also the desired efficacy leading to mCR attainment. Documentation of mCR even after previous exposure to Nivolumab, merits further investigation. Because of the limited existing data, the treatment duration and the exact dose of PD-1 inhibitors in the post alloSCT setting have not been clarified yet and therefore, well-designed prospective studies with large series of patients are warranted.\n==== Refs\nReferences\n\n1. Tsirigotis P Danylesko I Gkirkas K . Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant 2016;51 :1313-7.27183095\n2. Sala E Crocchiolo R Gandolfi S . Bendamustine combined with donor lymphocytes infusion in Hodgkin’s lymphoma relapsing after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2014;20 :1444-7.24907625\n3. Ansell SM Lesokhin AM Borrello I . PD-1 blockade with Nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015;372 :311-9.25482239\n4. Armand P Shipp MA Ribrag V . Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016;34 :3733-9.27354476\n5. Kasamon YL de Claro RA Wang Y . FDA Approval Summary: Nivolumab for the Treatment of Relapsed or Progressive Classical Hodgkin Lymphoma. Oncologist 2017; 22 :585-91.28438889\n6. Armand P Engert A Younes A . Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow- Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol 2018;36 :1428–39.29584546\n7. Armand P . Immune check-point blockade in hematologic malignancies. Blood 2015;125 :3393–400.25833961\n8. LaCasce AS Bociek RG Sawas A . Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood 2018;132 : 40–8.29703778\n9. Davis KL Fox E Merchant MS . Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 2020;21 :541-50 32192573\n10. Postow MA . Managing Immune Checkpoint-Blocking Antibody Side Effects. Am Soc Clin Oncol Educ Book 2015:76-83.25993145\n11. Kong Y Zhang J Claxton DF . PD- 1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J 2015;5 :e330.26230954\n12. Norde WJ Maas F Hobo W . PD- 1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res 2011;71 :5111-22.21659460\n13. Schnorfeil FM Lichtenegger FS Emmerig K . T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J Hematol Oncol 2015;8 :93.26219463\n14. Timmerman JM Engert A Younes A. . Checkmate 205 update with minimum 12-Month follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma. Blood 2016;128 :1110.\n15. Haverkos BM Abbott D Hamadani M . PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood 2017;130 :221–8.28468799\n16. Herbaux C Gauthier J Brice P . Efficacy and tolerability of Nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood 2017;129 :2471-8.28270452\n17. Godfrey J Bishop MR Syed S . PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J Immunother Cancer 2017;5 :11.28239465\n18. Armand P Engert A Younes A . Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow- Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol 2018;36 :1428-39.29584546\n19. Davids MS Kim HT Costello C . Optimizing check-point blockade as a Treatment for relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Blood 2017;130 :275.\n20. Onizuka M Kojima M Matsui K . Successful treatment with low-dose Nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Int J Hematol 2017;106 :141-5 28097534\n21. Herbaux C Merryman R Devine S . Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil. Blood 2018;132 :9-16.29720488\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "13(1)",
"journal": "Hematology reports",
"keywords": "Hodgkin lymphoma; allogeneic hematopoietic stem cell transplantation; programmed death-1 (PD-1) inhibitors",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "8780",
"pmc": null,
"pmid": "33747411",
"pubdate": "2021-03-05",
"publication_types": "D016428:Journal Article",
"references": "29584546;26219463;28270452;28438889;26230954;28468799;21659460;27183095;28097534;25482239;32192573;28239465;29720488;25993145;24907625;25833961;27354476;29703778",
"title": "Repeated courses of escalating doses of Nivolumab in refractory Hodgkin lymphoma with recurrent relapses post allografting: A safe and effective treatment approach.",
"title_normalized": "repeated courses of escalating doses of nivolumab in refractory hodgkin lymphoma with recurrent relapses post allografting a safe and effective treatment approach"
} | [
{
"companynumb": "SA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-292385",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "Since the development of antipsychotic drugs in the 1950s, a variety of studies and case reports have been published that suggest an association between exposure to typical antipsychotics and venous thromboembolisms (VTE). Therefore, when starting treatment with antipsychotics, especially low-potency typical antipsychotics and clozapine, health-care providers must account for the patient's existing VTE risk factors.\nIn this case report, the authors describe the development of a pulmonary embolism associated with use of chlorpromazine in the treatment of an acute manic episode in a 51-year-old female patient with bipolar disorder type 1.\nThe patient was brought to the emergency room by the police on a legal hold for bizarre behaviors at a bus stop, which included incessantly yelling at bystanders. The patient was found to have disorganized thoughts, poor sleep, rapid speech, labile mood, distractibility, auditory hallucinations and grandiose delusions. During the course of her stay, the patient received extensive IM chlorpromazine for extreme agitation, in addition to chlorpromazine 200 mg IM Q8H, which was later decreased to chlorpromazine 100 mg chlorpromazine IM/PO Q8H. On day 4 of the treatment, the patient experienced difficulty breathing, hypoxia and tachycardia and was found to have bilateral expiratory wheezes. CT angiography showed sub-segmental pulmonary embolus and the patient was transferred to MICU service. The patient was then intubated and started on heparin by the medical team. Over the course of the next day, her respiratory distress resolved and the patient was extubated.\nIt is possible that chlorpromazine may indeed increase VTEs, and there are various physiological postulations regarding the mechanism of action. However, multiple confounding variables existed in the authors' report, including venous stasis and the use of restraints, tobacco and valproic acid. Each of these variables has been shown to increase VTE occurrence. Further controlled studies are necessary to identify the true relationship between antipsychotics and VTEs.",
"affiliations": "Department of Psychiatry, University of California, Irvine, California, USA.;Department of Psychiatry, University of California, Irvine, California, USA.;Department of Psychiatry, University of California, Irvine, California, USA.;Department of Psychiatry, University of California, Irvine, California, USA.;Department of Psychiatry, University of California, Irvine, California, USA.;Department of Psychiatry, University of California, Irvine, California, USA.",
"authors": "Reed|Matthew Joseph|MJ|;Comeau|Sean|S|;Wojtanowicz|Todd R|TR|;Sampathi|Bharat Reddy|BR|;Penev|Sofia|S|;Bota|Robert|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1108/MIJ-10-2019-0005",
"fulltext": "\n==== Front\nMent Illn\nMIJ\n10.1108/MIJ\nMental Illness\n2036-7457\n2036-7465\nEmerald Publishing Limited\n\n32742621\n637194\n10.1108/MIJ-10-2019-0005\nResearch Paper\ncat-HSCHealth & social carecat-MHLTMental healthCase report: Chlorpromazine and deep venous thrombosis\nReed Matthew Joseph\nComeau Sean\nWojtanowicz Todd R.\nSampathi Bharat Reddy\nPenev Sofia\nBota Robert\nDepartment of Psychiatry, University of California, Irvine, California, USA\nCorresponding author: Robert Bota can be contacted at: rgbota@yahoo.com\n4 11 2019\n2019\n11 2 1619\n21 10 2019\n21 10 2019\n21 10 2019\n© Matthew Joseph Reed, Sean Comeau, Todd R. Wojtanowicz, Bharat Reddy Sampathi, Sofia Penev and Robert Bota.\n2019\nMatthew Joseph Reed, Sean Comeau, Todd R. Wojtanowicz, Bharat Reddy Sampathi, Sofia Penev and Robert Bota.\nhttps://creativecommons.org/licenses/by/4.0/ Published by Emerald Publishing Limited. This article is published under the Creative Commons Attribution (CC BY 4.0) licence. Anyone may reproduce, distribute, translate and create derivative works of this article (for both commercial and non-commercial purposes), subject to full attribution to the original publication and authors. The full terms of this licence may be seen at: http://creativecommons.org/licences/by/4.0/legalcode\n\nPurpose\n\nSince the development of antipsychotic drugs in the 1950s, a variety of studies and case reports have been published that suggest an association between exposure to typical antipsychotics and venous thromboembolisms (VTE). Therefore, when starting treatment with antipsychotics, especially low-potency typical antipsychotics and clozapine, health-care providers must account for the patient’s existing VTE risk factors.\n\nDesign/methodology/approach\n\nIn this case report, the authors describe the development of a pulmonary embolism associated with use of chlorpromazine in the treatment of an acute manic episode in a 51-year-old female patient with bipolar disorder type 1.\n\nFindings\n\nThe patient was brought to the emergency room by the police on a legal hold for bizarre behaviors at a bus stop, which included incessantly yelling at bystanders. The patient was found to have disorganized thoughts, poor sleep, rapid speech, labile mood, distractibility, auditory hallucinations and grandiose delusions. During the course of her stay, the patient received extensive IM chlorpromazine for extreme agitation, in addition to chlorpromazine 200 mg IM Q8H, which was later decreased to chlorpromazine 100 mg chlorpromazine IM/PO Q8H. On day 4 of the treatment, the patient experienced difficulty breathing, hypoxia and tachycardia and was found to have bilateral expiratory wheezes. CT angiography showed sub-segmental pulmonary embolus and the patient was transferred to MICU service. The patient was then intubated and started on heparin by the medical team. Over the course of the next day, her respiratory distress resolved and the patient was extubated.\n\nOriginality/value\n\nIt is possible that chlorpromazine may indeed increase VTEs, and there are various physiological postulations regarding the mechanism of action. However, multiple confounding variables existed in the authors’ report, including venous stasis and the use of restraints, tobacco and valproic acid. Each of these variables has been shown to increase VTE occurrence. Further controlled studies are necessary to identify the true relationship between antipsychotics and VTEs.\n\nClozapine\nRisk factors\nAntipsychotic drugs\nBipolar disorder\nChlorpromazine\nVenous thromboembolisms\ncopyright-codeZ\ndeliverablesWeb-ready article package\npeer-reviewedYes\nacademic-contentYes\nEContentTypeJOURNAL\nrightslinkexcluded\n==== Body\npmcIntroduction\n\nSince the development of antipsychotic drugs in the 1950s, a variety of studies and case reports have been published that suggest an association between exposure to typical antipsychotics and venous thromboembolism (VTE). Such an association has also been identified with Clozapine (Walker et al., 1997). VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE), which can be fatal. Therefore, when starting treatment with antipsychotics, especially low-potency typical antipsychotics and clozapine, health care providers must account for the patient’s existing VTE risk factors. Clinicians should consider interrupting or changing the antipsychotic regimen in patients in whom this adverse effect is suspected, such as in patients with chest pain, dyspnea or oxygen desaturation. More studies are currently required to determine the incidence rate, the possible predisposing factors and the biological mechanisms involved.\n\nIn several studies, such as by Parkin et al. (2003) and Zornberg and Jick (2000), low-potency antipsychotics, such as the phenothiazines, were shown to be more strongly associated with increased risk for VTE than high-potency antipsychotics, such as haloperidol. Several hypotheses have been proposed for the biological mechanisms by which antipsychotics may portend increased VTE risk, including: elevation of anticardiolipin autoantibodies (Canoso et al., 1990), enhanced platelet aggregation (Zornberg and Jick, 2000) venous stasis caused by sedation and hyperhomocysteinemia (Ray et al., 2002). We cannot exclude the possibility that the underlying psychiatric disorders themselves are associated with thromboembolic phenomena. In fact, this link has been made by a number of studies, which discuss VTE risk factors present in psychiatric disorders, which are independent of pharmacotherapy, such as increased adrenaline secretion during acute psychotic episodes (Hindersin et al., 1984), use of physical restraints (Lazarus, 2001), increased frequency of smoking in patients with schizophrenia (Hughes et al., 1986) as well as abnormal phospholipid metabolism and autoimmunity in schizophrenia (Halacheva et al., 2009).\n\nIn this case report, we describe the development of a PE associated with use of chlorpromazine in the treatment of an acute manic episode in a patient with a diagnosis of bipolar disorder type 1.\n\nCase report\n\nA 51-year-old female with self-reported bipolar disorder presented to the emergency room brought in by police for bizarre behaviors at a bus stop, which included incessantly yelling at bystanders. She was found to have disorganized thoughts, poor sleep, rapid speech, labile mood, distractibility, auditory hallucinations and grandiose delusions. A 5,150 hold was placed and patient was started on olanzapine 10 mg BID, clonazepam 0.5 mg BID and olanzapine 5 mg Q6H PRN for agitation. Of note, the patient had flu-like symptoms and a positive influenza swab and was subsequently started on oseltamivir. The patient was confined to the ED as there were no psychiatric inpatient units that could accommodate droplet precautions at the time. She was also too disorganized to trust her with an infection prevention mask.\n\nDay 2: While in the emergency room, the patient required multiple rounds of emergency medications because of agitation, aggression and inability to redirect from staff on the first night. These included two rounds of haloperidol 5 mg + lorazepam 2 mg + diphenhydramine 50 mg IM, olanzapine 5 mg PO × 1 and chlorpromazine 50 mg IM × 1. Because of no apparent change in her behavior, the standing olanzapine dose was increased to 15 mg PO BID and clonazepam 1 mg PO BID.\n\nDay 3: The patient continued to require multiple rounds of emergency medications as she was not responding to olanzapine 5 mg PRN for agitation with two additional rounds of haloperidol 5 mg + lorazepam 2 mg + diphenhydramine 50 mg IM need overnight. Because of lack of response from IM emergency medication cocktail, the emergency medication recommendation was changed to chlorpromazine 100 mg PO/IM + lorazepam 1 mg PO/IM. Also, valproic acid 500 mg QAM + 1000 mg QHS PO was added for additional mood stabilization.\n\nDay 4: Patient was placed on a 5,250 hold as she continued to appear gravely disabled. Overnight, the patient was reported to be extremely agitated, demanding and not verbally redirectable. Patient required prns of Zyprexa 5 mg × 2 and emergency medications chlorpromazine 100 mg and lorazepam 1 mg IM with no significant effect on her behavior or symptomatology. The emergency medication was changed to offer PO chlorpromazine 200 mg Q8H and lorazepam 1 mg Q8H, if refused then chlorpromazine 200 mg IM Q8H (divided) + lorazepam 1 mg IM Q8H for agitation (2nd line). After 2 days on this regimen, the patient became increasingly somnolent so the regimen was changed back to chlorpromazine 100 mg PO/IM + lorazepam 1 mg PO/IM. However, the patient continued to be increasingly somnolent. She also demonstrated slurred speech, which was thought to be related to emergency medications and poor sleep.\n\nOn the day the patient was medically cleared for psychiatric hospitalization, she was reported by the ED nurse to have difficulty breathing in the ED becoming hypoxic and tachycardia. She was found to have bilateral expiratory wheezes on physical examination and was treated with ipratropium bromide 0.5 mg/albuterol sulfate 3.0 mg. Chest X-ray obtained showed possible left-sided pneumonia. Patient was given IV rocephin and azithromycin and fluids. CT angio done to rule out PE and the patient was admitted to medicine for pneumonia.\n\nOn admission to medicine, the patient had a valproic acid level of 166 mcg/ml. The patient was noted becoming increasingly agitated with respiratory distress. As she was altered and unable to tolerate BiPAP, she was intubated for airway protection and hypoxic respiratory failure. By this time, the CT angiography showed sub-segmental pulmonary embolus and the patient was transferred to MICU service. There she was determined to have combined hypercarbic and hypoxic respiratory failure secondary to COPD exacerbation with influenza, possible hospital-acquired pneumonia given prolonged hospital stay and possible PE given immobility in ED, tachycardia and high Well’s score. She was then started on heparin by the medical team and over the course of the next day, her respiratory distress resolved and she was extubated.\n\nDiscussion\n\nIt has been noted in multiple studies that the specific use of chlorpromazine may increase VTE occurrences. From 1953 to 1977, after the discovery of chlorpromazine’s antipsychotic effects, the literature in Germany indicated that antipsychotic use may lead to fatal PE. In one study from 1954 to 1957, 11 out of 338 phenothiazine users died from PEs compared to just one in the non-phenothiazine group (Masopust et al., 2012). In a more recent study, Zornberg and Jick analyzed 29,952 antipsychotic medication users and calculated an odds ratio of 3.3 for high-potency antipsychotics and 24.1 for low-potency antipsychotics such as chlorpromazine in regards to PE outcomes (Zornberg and Jick, 2000).\n\nAnticardiolipin antibodies have been identified as a possible contributor to thrombosis. Roche-Bayard et al. presented a case of chlorpromazine-induced lupus erythematosus that resulted in multiple thromboembolic events and eventually a PE. Laboratory tests for this patient showed increased IgM and IgG anticardiolipin antibodies, antiprothombinase-type circulating anticoagulant, and decreased factors VII, IX and XI (Roche-Bayard et al., 1990). Furthermore, a few studies have indicated that chlorpromazine use can lead to 5-HT induced platelet aggregation. However, these results have since been unreplaceable and later studies reported that noradrenaline increases 5-HT induced aggregation. Therefore, it is possible that the 5-HT enhancement is because of elevated plasma noradrenaline in stressed schizophrenics that were concurrently treated with chlorpromazine (Orr and Boullin, 1976) Venous stasis can also occur in patients on antipsychotics because of the sedative effects of the drugs. Finally, one study has suggested that increased homocysteine levels as a byproduct of antipsychotic use can lead to VTEs as well (Ray et al., 2002).\n\nIt is important to identify the variables that confound the relationship between chlorpromazine and VTEs. Reviews have identified a positive correlation between prolonged immobilization from physical restraints and VTE, even without other DVT risk factors (De Hert et al., 2010). Furthermore, chronic smokers are at an increased risk of VTEs, and a study by Hughes et al. found that smoking was significantly high in psychiatric patients when compared to a random population-based sample of 1,140 Minnesotans and 17,000 US citizens (52 per cent vs 30 per cent vs 33 per cent, respectively). Among the psychiatric patients, smoking was especially high in mania (70 per cent) (Hughes et al., 1986).\n\nAnother possible relationship between chlorpromazine and VTE may include concurrent Depakote use. A study in 2005 concluded that Depakote may potentiate typical and atypical antipsychotics leading to increased prefrontal dopamine release via 5-HT (1 A) receptor activation (Ichikawa et al., 2005). Given past studies stating that chlorpromazine may cause platelet aggregation via 5-HT receptor activation, the use of valproic acid may indirectly increase VTEs in patients with simultaneous antipsychotic use.\n\nOur case report provides important insight into the possible association between chlorpromazine and VTEs and the confounding variables. During the course of her stay, our patient received extensive IM chlorpromazine for extreme agitation in addition to chlorpromazine 200 mg IM Q8H, which was later decreased to chlorpromazine 100 mg chlorpromazine IM/PO Q8H. Given the large cumulative dosing of chlorpromazine during the patient’s hospitalization, it is a possibility that chlorpromazine itself led to the patients VTE based the studies mentioned above. However, the patient was very sedated and in restraints for a lengthy period leading to both prolonged immobility and venous stasis. This may have led to her PE. Furthermore, the patient is a chronic tobacco user, another factor known to increase clotting. Presenting with symptoms of mania, elevated noradrenaline levels could have also contributed to her PE. Finally, if it is true that valproic acid potentiates the effects of antipsychotics, an increased level of 166 mcg/ml may have led to higher chlorpromazine concentrations than desired, contributing to her PE. Retrospectively, it would have been useful to record the patient’s homocysteine level given data that increased homocysteine may cause clotting. It is also important to note that the patient was an extremely poor historian and it is unclear if she had underlying comorbidities contributing to her PE, including hypercholesterolemia and chronic hypertension.\n\nConclusion\n\nIn this case report, we describe the development of a PE associated with chlorpromazine use in the treatment of an acute manic episode in a bipolar type 1 patient. In conclusion, chlorpromazine may indeed increase VTEs, but multiple variables confound the ability to elucidate the degree of effect. Further controlled studies are needed to make progress in this long-standing debate.\n==== Refs\nReference\n\nCanoso, R.T., de Oliveira, R.M. and Nixon, R.A. (1990), “Neuroleptic-associated autoantibodies. A prevalence study”, Biological Psychiatry, Vol. 27 No. 8 , pp. 863-870.1970485\nDe Hert, M., Einfinger, G. and Scherpenberg, E. et al. (2010), “The prevention of deep venous thrombosis in physically restrained patients with schizophrenia”, International Journal of Clinical Practice, Vol. 64 No. 8 , pp. 1109-1115, doi: 10.1111/j.1742-1241.2010.02380.x.20642709\nHalacheva, K., Dimova, S. and Tolev, T., Dimov, D. and Nikolova, M. (2009), “Elevated anticardiolipin antibodies in schizophrenic patients before and during neuroleptic medication”, Psychiatry Research , Vol. 169 No. 1 , pp. 51-55, doi: 10.1016/j.psychres.2008.05.011.19596154\nHindersin, P., Siegmund, R. and Korting, H.J. (1984), “Thrombophilic diatheses as hemostasis disorders in acute psychoses]”, Psychiatr Neurol Med Psychol (Leipz), Vol. 36 No. 12 , pp. 702-709.6528003\nHughes, J.R., Hatsukami, D.K., Mitchell, J.E. and Dahlgren, L.A. (1986), “Prevalence of smoking among psychiatric outpatients”, The American Journal of Psychiatry , Vol. 143 No. 8 , pp. 993-997, doi: 10.1176/ajp.143.8.993.3487983\nIchikawa, J., Chung, Y.C., Dai, J. and Meltzer, H.Y. (2005), “Valproic acid potentiates both typical and atypical antipsychotic-induced prefrontal cortical dopamine release”, Brain Research , Vol. 1052 No. 1 , available at: 10.1016/j.brainres.2005.06.009\nLazarus, A. (2001), “Physical restraints, thromboembolism, and death in 2 patients”, The Journal of Clinical Psychiatry , Vol. 62 No. 3 , pp. 207-208.11305711\nMasopust, J., Malý, R. and Vališ, M. (2012), “Risk of venous thromboembolism during treatment with antipsychotic agents”, Psychiatry and Clinical Neurosciences, Vol. 66 No. 7 , available at: 10.1111/pcn.12001\nOrr, M. and Boullin, D. (1976), “The ralationship between changes in 5‐HT induced platelet aggregation and clinical state in patients treated with fluphenazine”, British Journal of Clinical Pharmacology, Vol. 3 No. 5 , available at: 10.1111/j.1365-2125.1976.tb00648.x\nParkin, L., Skegg, D.C. and Herbison, G.P. et al. (2003), “Psychotropic drugs and fatal pulmonary embolism”, Pharmacoepidemiology and Drug Safety, Vol. 12 No. 8 , pp. 647-652., doi: 10.1002/pds.841.doi:14762980\nRay, J.G., Mamdani, M.M. and Yeo, E.L. (2002), “Antipsychotic and antidepressant drug use in the elderly and the risk of venous thromboembolism”, Thrombosis and Haemostasis , Vol. 88 No. 2 , pp. 205-209.12195690\nRoche-Bayard, P., Rossi, R., Mann, J.M., Cordier, J.F. and Delahaye, J.P. (1990), “Left pulmonary artery thrombosis in chlorpromazine-induced lupus”, Chest, Vol. 98 No. 6 , available at: 10.1378/chest.98.6.1545a\nWalker, A.M., Lanza, L.L. and Arellano, F. et al. (1997), “Mortality in current and former users of clozapine”, Epidemiology, Vol. 8 No. 6 , pp. 671-677.9345668\nZornberg, G.L. and Jick, H. (2000), “Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study”, The Lancet, Vol. 356 No. 9237 , pp. 1219-1223., doi: 10.1016/S0140-6736(00)02784-7.\nFurther reading\n\nBesag, F.M. and Berry, D. (2006), “Interactions between antiepileptic and antipsychotic drugs”, Drug Safety, Vol. 29 No. 2 , pp. 95-118.16454538\nGerstner, T., Teich, M. and Bell, N. et al. (2006), “Valproate-associated coagulopathies are frequent and variable in children”, Epilepsia, Vol. 47 No. 7 , pp. 1136-1143., doi: 10.1111/j.1528-1167.2006.00587.x.16886976\nUndas, A., Brozek, J. and Szczeklik, A. (2005), “Homocysteine and thrombosis: from basic science to clinical evidence”, Thromb Haemost, Vol. 94 No. 5 , pp. 907-915, doi: 10.1160/TH05-05-0313.16363230\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2036-7457",
"issue": "11(2)",
"journal": "Mental illness",
"keywords": "Antipsychotic drugs; Bipolar disorder; Chlorpromazine; Clozapine; Risk factors; Venous thromboembolisms",
"medline_ta": "Ment Illn",
"mesh_terms": null,
"nlm_unique_id": "101634942",
"other_id": null,
"pages": "16-19",
"pmc": null,
"pmid": "32742621",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "2245719;9345668;23252920;14762980;16886976;11072939;973988;1970485;16454538;19596154;16061211;11305711;20642709;6528003;16363230;3487983;12195690",
"title": "Case report: Chlorpromazine and deep venous thrombosis.",
"title_normalized": "case report chlorpromazine and deep venous thrombosis"
} | [
{
"companynumb": "US-UNICHEM PHARMACEUTICALS (USA) INC-UCM202005-000646",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"... |
{
"abstract": "A 70-year-old Indian woman, who had undergone primary bilateral total knee arthroplasty (TKA) for rheumatoid arthritis 10 months prior, presented with 10 days history of pain, swelling and erythema over both knees with pus discharging from the right knee. She had type 2 diabetes mellitus and was on long-term steroid, leflunomide and antitumour necrosis factor therapy for rheumatoid arthritis. Her clinical and laboratory features were suggestive of a haematogenous periprosthetic joint infection (PJI). The final diagnosis of bilateral Salmonella typhi PJI was made based on culture reports. Considering her underlying immunosuppression, a bilateral two-stage revision TKA was done with complete remission of symptoms and good functional recovery at last follow-up after 18 months. S. typhi infection of prosthetic joint has not been reported in the literature. Patients presenting with gastrointestinal complaints and PJI should alert the clinician to the possibility of infection with such atypical organisms endemic to the region.",
"affiliations": "Department of Orthopaedics, Fortis Escorts Bone and Joint Institute, New Delhi, Delhi, India.;Department of Orthopaedics, Fortis Escorts Bone and Joint Institute, New Delhi, Delhi, India.;Department of Microbiology, Fortis Escorts Heart Institute, New Delhi, Delhi, India.",
"authors": "Rajgopal|Ashok|A|;Panda|Inayat|I|http://orcid.org/0000-0002-3774-9678;Gupta|Anu|A|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221221",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "biological agents; bone and joint infections; foodborne infections; orthopaedic and trauma surgery; rheumatoid arthritis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D019645:Arthroplasty, Replacement, Knee; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007719:Knee Joint; D016459:Prosthesis-Related Infections; D011859:Radiography; D012086:Reoperation; D012480:Salmonella Infections; D012486:Salmonella typhimurium; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29141925",
"pubdate": "2017-11-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24749773;25424009;18421542;12199853;15483283;21301900;19897369;15298225;2259871;20545918;22118951;15315049;24133312;27082958;333539;11284255;7073124;3306260;10403266;9370874;16642625;15804667;19269872;26662756;19692690;26425605;19326836;11157155;23311895;1475635",
"title": "Unusual Salmonella typhi periprosthetic joint infection involving bilateral knees: management options and literature review.",
"title_normalized": "unusual salmonella typhi periprosthetic joint infection involving bilateral knees management options and literature review"
} | [
{
"companynumb": "IN-EDENBRIDGE PHARMACEUTICALS, LLC-IN-2017EDE000241",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"dru... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset.\n\n\nMETHODS\nA retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables.\n\n\nRESULTS\nA total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%).\n\n\nCONCLUSIONS\nAA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.",
"affiliations": "Departments of *Medical Oncology ‡Urology §Prostate Programme, Fondazione IRCCS Istituto Nazionale dei Tumori †Mario Negri Institute for Pharmacological Research, Milan, Italy.",
"authors": "Procopio|Giuseppe|G|;Grassi|Paolo|P|;Testa|Isabella|I|;Verzoni|Elena|E|;Torri|Valter|V|;Salvioni|Roberto|R|;Valdagni|Riccardo|R|;de Braud|Filippo|F|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D000069501:Abiraterone Acetate; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0b013e3182a790ce",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "38(5)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002318:Cardiovascular Diseases; D015897:Comorbidity; D000077143:Docetaxel; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "479-82",
"pmc": null,
"pmid": "24064757",
"pubdate": "2015-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.",
"title_normalized": "safety of abiraterone acetate in castration resistant prostate cancer patients with concomitant cardiovascular risk factors"
} | [
{
"companynumb": "IT-JNJFOC-20150919459",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnaphylaxis during general anaesthesia is rare but often severe. Identification of the cause of anaphylaxis and recommendation of a range of drugs or agents likely to be safer for future surgery is a collaborative venture between the allergists and the anaesthesiologists, but it often poses a significant challenge.\n\n\nMETHODS\nA total of 31 patients who attended the Drug Allergy Unit at University College London Hospital with suspected perioperative anaphylaxis between March 2013 and January 2016 were reviewed retrospectively.\n\n\nRESULTS\nThe culprit drug was identified in 21 patients (67.7%): antibiotics (n = 11, 52.3%), neuromuscular blocking agents (n = 8, 38.1%), morphine (n = 1, 4.8%) and gelofusine (n = 1, 4.8%). No cause was identified in six patients (19.4%), and four patients (12.9%) had non-allergic reactions.\n\n\nCONCLUSIONS\nOur results confirm that antibiotics and neuromuscular blocking agents are common causative agents of perioperative anaphylaxis in the United Kingdom.",
"affiliations": "Otolaryngology Department, West China Hospital, Sichuan University, Chengdu, China.;Department of Specialist Allergy and Clinical Immunology, Royal National Throat Nose Ear Hospital, University College London Hospital, London, UK.;Department of Anaesthetics, University College London Hospital, London, UK.;Department of Specialist Allergy and Clinical Immunology, Royal National Throat Nose Ear Hospital, University College London Hospital, London, UK.",
"authors": "Meng|J|J|;Rotiroti|G|G|;Burdett|E|E|;Lukawska|J J|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D009466:Neuromuscular Blocking Agents",
"country": "England",
"delete": false,
"doi": "10.1111/aas.12858",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "61(3)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000707:Anaphylaxis; D000768:Anesthesia, General; D000900:Anti-Bacterial Agents; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D020315:Latex Hypersensitivity; D008297:Male; D008875:Middle Aged; D009466:Neuromuscular Blocking Agents; D012189:Retrospective Studies; D012882:Skin Tests",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "281-289",
"pmc": null,
"pmid": "28164272",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis during general anaesthesia: experience from a drug allergy centre in the UK.",
"title_normalized": "anaphylaxis during general anaesthesia experience from a drug allergy centre in the uk"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201702752",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nWith the availability of the once daily oral antimuscarinic agent solifenacin (5 mg), we started to use it for therapy resistant overactive bladder. We evaluate side effects and efficacy.\n\n\nMETHODS\nWe reviewed the charts of children treated with solifenacin succinate between August 2005 and August 2008 for therapy resistant OAB. Incontinence was compared at study entry and study end.\n\n\nRESULTS\nDuring the study period 84 boys and 54 girls with a mean age of 9 years 2 months received solifenacin. Mean followup was 22.59 months. While on solifenacin, side effects were observed in 9 of 138 patients (6.5%). Efficacy evaluation included only 99 patients after 3 months of therapy. Mean voided volume after treatment was 253.5 ml, showing a significant 25% increase compared to the mean value before therapy (50.5 vs 203.0 ml, p <0.01). Of the patients 84 (85%) were considered responders, including 45 who were completely dry (full response) and 39 who had fewer nocturnal enuresis or diurnal incontinence symptoms (partial response). Of these 39 patients 17 became dry during the day, 1 became dry during the night and 21 had more than a 50% decrease in nocturnal enuresis and diurnal incontinence symptoms. In 15 patients the outcome was unchanged or worse (no response).\n\n\nCONCLUSIONS\nIn this group of children with OAB we noted favorable results with solifenacin with few side effects. Despite the uncontrolled, retrospective study design the effect is attributable to solifenacin intake.",
"affiliations": "Division of Pediatric Urology, Department of Urology, Ghent University Hospital, Ghent, Belgium. Piet.hoebeke@ugent.be",
"authors": "Hoebeke|Piet|P|;De Pooter|Jan|J|;De Caestecker|Karel|K|;Raes|Ann|A|;Dehoorne|Joke|J|;Van Laecke|Erik|E|;Vande Walle|Johan|J|",
"chemical_list": "D018727:Muscarinic Antagonists; D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D000069464:Solifenacin Succinate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.juro.2009.05.100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-5347",
"issue": "182(4 Suppl)",
"journal": "The Journal of urology",
"keywords": null,
"medline_ta": "J Urol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D012189:Retrospective Studies; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines; D016896:Treatment Outcome; D053201:Urinary Bladder, Overactive",
"nlm_unique_id": "0376374",
"other_id": null,
"pages": "2040-4",
"pmc": null,
"pmid": "19695608",
"pubdate": "2009-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Solifenacin for therapy resistant overactive bladder.",
"title_normalized": "solifenacin for therapy resistant overactive bladder"
} | [
{
"companynumb": "BE-ASTELLAS-2017US011148",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOLIFENACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Propofol is a common induction agent that is utilized worldwide in the field of anesthesiology. In recent years, its potential therapeutic role in a variety of patient states has been demonstrated. Controversy exists regarding Propofol mediated analgesic and antihyperalgesic properties. Recent studies have suggested a variety of different mechanisms of action, including modulation of N-Methyl-D- Aspartate receptors and the endocannabinoid system. The N-Methyl-D- Aspartate receptor is part of a larger family of glutamate receptors and is an important mediator of excitatory neurotransmission. In the case presented, the pain experienced by the patient was not well-controlled, in spite of increasing doses of opioids, potentially due to superimposed opioid induced hyperalgesia. In the present case, we demonstrate a cycle of opioid induced hyperalgesia which was successfully affected with a Propofol infusion. Controversial reports exist in animal studies on the analgesic properties of Propofol. Randomized controlled studies in animal models studying the effect of Propofol on pain sensation have shown that Propofol possesses an analgesic effect. This clinical case demonstrates that Propofol could possibly have antihyperalgesic effects on opioid induced hyperalgesia caused by high-doses of chronic opioids and worsened by fentanyl. We postulate that a probable mechanism of complete pain relief after the procedure could be the inhibition of activity of the N-Methyl-D- Aspartate receptor by Propofol because it was the only agent the patient received during the procedure, causing a break of the cycle of opioid induced hyperalgesia. Additional research is required to clarify Propofol mediated or modulated analgesic properties in humans.",
"affiliations": "Department of Anesthesiology, LSU School of Medicine, New Orleans, LA.",
"authors": "Kaye|Alan D|AD|;Chung|Keun Sam|KS|;Vadivelu|Nalini|N|;Cantemir|Catalin|C|;Urman|Richard D|RD|;Manchikanti|Laxmaiah|L|",
"chemical_list": "D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "17(2)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D059350:Chronic Pain; D006801:Humans; D006930:Hyperalgesia; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1; D015742:Propofol",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "E225-8",
"pmc": null,
"pmid": "24658490",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opioid induced hyperalgesia altered with propofol infusion.",
"title_normalized": "opioid induced hyperalgesia altered with propofol infusion"
} | [
{
"companynumb": "PHHY2015US083747",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugad... |
{
"abstract": "BACKGROUND\nGranulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease.\n\n\nMETHODS\nPathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases.\n\n\nRESULTS\nThe granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis.\n\n\nCONCLUSIONS\nIn our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.",
"affiliations": "Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School, Houston, TX 77030, USA.;Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School, Houston, TX 77030, USA.;Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School, Houston, TX 77030, USA.;Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.;Department of Internal Medicine, University of Texas McGovern Medical School, Houston, TX 77030, USA; Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.;Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.;Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School, Houston, TX 77030, USA. Electronic address: L.Maximilian.Buja@uth.tmc.edu.",
"authors": "Sadaf|Humaira|H|;Zhao|Bihong|B|;Lelenwa|Laura C|LC|;Patel|Manish K|MK|;Jyothula|Soma S|SS|;Gregoric|Igor D|ID|;Buja|L Maximilian|LM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.anndiagpath.2021.151832",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-9134",
"issue": "55()",
"journal": "Annals of diagnostic pathology",
"keywords": "Chronic lung disease; Fungal infection; Granulomatous lesion; Lung transplantation; Transplant rejection",
"medline_ta": "Ann Diagn Pathol",
"mesh_terms": null,
"nlm_unique_id": "9800503",
"other_id": null,
"pages": "151832",
"pmc": null,
"pmid": "34628284",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation.",
"title_normalized": "granulomatous fungal and non tuberculous mycobacterial infestation complicating chronic lung disease outcomes in patients undergoing lung transplantation"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP003746",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "Many patients with immune thrombocytopenia (ITP) may require special attention and long-term treatment. Little is known on the efficacy and tolerability of the drugs used in practice.\n\n\n\nWe retrospectively reviewed the results of therapy of 400 patients with chronic ITP. All Patients were treated at our institution between 1996-2016 under consideration of guidelines, general recommendations, and individual aspects, including gender, age, weight, comorbidity, patient's medical history and bleeding risk.\n\n\n\nTreatment was not required in 25% of patients (n = 100) during observation. In treated patients (n = 300), the rate of patients that responded and tolerated treatment with prednisolone was 59% (52/88), with azathioprine 32% (29/90), with eltrombopag 49% (31/63), with romiplostim 59% 27/45, with IVIG (intravenous immunoglobulines) 75% (94/126), with anti-D 37% (19/52) and with dexamethasone 60% (25/42) patients. Eighteen treated patients (6%) entered sustained remission after treatment with various drugs. Twenty-six patients underwent splenectomy (Splx) resulting in sustained remission in 15 cases (60%). Only two patients remained refractory to Splx and to all used drugs.\n\n\n\nNone of the currently available drugs used in the treatment of ITP are invariably safe and effective. Responses, the duration of response, intolerability, and the course of disease are unpredictable. Although the treatment of ITP has considerably improved in the recent years, the currently available drugs may rarely cure affected patients. The need for safe and effective therapy in ITP is evident. Optimal treatment decisions for each patient remains a challenge in many cases.",
"affiliations": "Institute of Transfusion Medicine, Charité Unversitätsmedizin Berlin, Berlin, Germany.;Institute of Transfusion Medicine, Charité Unversitätsmedizin Berlin, Berlin, Germany.;Institute of Transfusion Medicine, Charité Unversitätsmedizin Berlin, Berlin, Germany.;Institute of Transfusion Medicine, Charité Unversitätsmedizin Berlin, Berlin, Germany.",
"authors": "Depré|Fabian|F|;Aboud|Nasra|N|;Mayer|Beate|B|;Salama|Abdulgabar|A|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D011720:Pyrazoles; C061961:RHO(D) antibody; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D018029:Rho(D) Immune Globulin; D000069283:Rituximab; D003907:Dexamethasone; D016572:Cyclosporine; D003622:Dapsone; D013926:Thrombopoietin; D011239:Prednisolone; C488777:romiplostim; D001379:Azathioprine; C520809:eltrombopag",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0198184",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0198184PONE-D-17-27886Research ArticleMedicine and Health SciencesClinical MedicineClinical ImmunologyAutoimmune DiseasesIdiopathic Thrombocytopenic PurpuraBiology and Life SciencesImmunologyClinical ImmunologyAutoimmune DiseasesIdiopathic Thrombocytopenic PurpuraMedicine and Health SciencesImmunologyClinical ImmunologyAutoimmune DiseasesIdiopathic Thrombocytopenic PurpuraMedicine and Health SciencesHematologyThrombocytopeniaIdiopathic Thrombocytopenic PurpuraMedicine and Health SciencesPharmaceuticsDrug TherapyMedicine and Health SciencesPharmacologyAdverse ReactionsBiology and Life SciencesAnatomyBody FluidsBloodPlateletsMedicine and Health SciencesAnatomyBody FluidsBloodPlateletsBiology and Life SciencesPhysiologyBody FluidsBloodPlateletsMedicine and Health SciencesPhysiologyBody FluidsBloodPlateletsBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsPlateletsMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsHemorrhageMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsHemorrhageMedicine and Health SciencesVascular MedicineHemorrhageMedicine and Health SciencesPharmaceuticsDrug TherapySteroid TherapyMedicine and Health SciencesSurgical and Invasive Medical ProceduresBlood and Lymphatic System ProceduresSplenectomyMedicine and Health SciencesPharmacologyDrugsImmunosuppressivesEfficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia: Results from a long-term observation in clinical practice Treatment of ITPDepré Fabian ConceptualizationData curationInvestigationVisualizationWriting – original draft12Aboud Nasra Formal analysisInvestigation1Mayer Beate SupervisionWriting – review & editing1Salama Abdulgabar Data curationSupervisionWriting – review & editing1*1 \nInstitute of Transfusion Medicine, Charité Unversitätsmedizin Berlin, Berlin, Germany2 \nDepartment of Cardiology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, GermanyColombo Gualtiero I. EditorCentro Cardiologico Monzino, ITALYCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: abdulgabar.salama@charite.de1 6 2018 2018 13 6 e019818426 7 2017 15 5 2018 © 2018 Depré et al2018Depré et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nMany patients with immune thrombocytopenia (ITP) may require special attention and long-term treatment. Little is known on the efficacy and tolerability of the drugs used in practice.\n\nMaterial and methods\nWe retrospectively reviewed the results of therapy of 400 patients with chronic ITP. All Patients were treated at our institution between 1996–2016 under consideration of guidelines, general recommendations, and individual aspects, including gender, age, weight, comorbidity, patient’s medical history and bleeding risk.\n\nResults\nTreatment was not required in 25% of patients (n = 100) during observation. In treated patients (n = 300), the rate of patients that responded and tolerated treatment with prednisolone was 59% (52/88), with azathioprine 32% (29/90), with eltrombopag 49% (31/63), with romiplostim 59% 27/45, with IVIG (intravenous immunoglobulines) 75% (94/126), with anti-D 37% (19/52) and with dexamethasone 60% (25/42) patients. Eighteen treated patients (6%) entered sustained remission after treatment with various drugs. Twenty-six patients underwent splenectomy (Splx) resulting in sustained remission in 15 cases (60%). Only two patients remained refractory to Splx and to all used drugs.\n\nDiscussion\nNone of the currently available drugs used in the treatment of ITP are invariably safe and effective. Responses, the duration of response, intolerability, and the course of disease are unpredictable. Although the treatment of ITP has considerably improved in the recent years, the currently available drugs may rarely cure affected patients. The need for safe and effective therapy in ITP is evident. Optimal treatment decisions for each patient remains a challenge in many cases.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nAlmost 100 years have passed since the establishment of splenectomy (Splx) as the first and still successfully used therapeutic measure in management of immune thrombocytopenia (ITP) [1]. The second therapeutic measure available for ITP patients was cortisone, which became available in 1951 [2], and was later on replaced by modified and less toxic steroids [3]. Since the 1960’s, immunosuppressive drugs including azathioprine, cyclophosphamide, vincristine and vinblastine have been used, but their use remains limited in ITP [4]. A new era in the treatment of ITP was established in 1981 with the observation that intravenous immunoglobulins (IVIG) resulted in an unexpected increase in platelet counts (plc) in children with ITP [5, 6]. Soon thereafter, a fourth alternative was incorporated into the list of therapeutic options in ITP: anti-D [7]. The late 1990s saw the introduction of rituximab [8], whereas the turn of the new century was influenced by well-designed studies using thrombopoietin receptor agonists (TPO-RA) [9–12]. Although the list of available drugs in the treatment of ITP is growing, there remain several unsatisfactory aspects [13]. These include the results and comments of several reviews and reports dealing with ITP management and outcomes [4, 14–22] and various guidelines on the management of ITP [23–26]. The recommendations are somewhat arbitrary and cannot be applied in many cases [14, 18, 26–29]. In addition, many factors including ethnicity [30, 31], subjective opinion, and conflict of interest may play a role in the management of ITP. Ultimately, there is no specific curative treatment for autoimmune diseases. The present study focuses on the long-term efficacy and safety of drugs used in the treatment of patients with ITP in our institute during the last two decades. The results clearly indicate that the treatment of ITP has improved, but still should be replaced by more specific and safe drugs.\n\nMaterials and methods\nData from 400 patients (398 adults, and 2 children; 143 males and 257 females) with a mean age of 50.5 years (range, 3–101 years) that were diagnosed with chronic ITP [32], between 1964 and 2015 were retrospectively reviewed and analyzed to assess the efficacy and safety of the used therapies. All patients were treated on an outpatient basis at our institution by a single physician between 1996 and 2016. Standard dose of therapeutic agents was used (Prednisolone 0,5–1 mg/kg/d for 1–3 weeks, ≤ 7,5 mg/d for >3 weeks; Dexamethasone 40 mg/d for 4 days (1–6 cycles every 14–28 days); IVIG 0,4–2 g/kg; Anti-D 50–75 μg/kg; Rituximab 375 mg/m2/week for 4 times; Splx laparoscopic; Azathioprine 1-2mg/kg/d; Eltrombopag 50–75 mg/d; Romiplostim 1–10 μg/kg/week; Dapsone 75–100 mg/d; Cyclophosphamide 1–2 mg/kg/d p.o., 0,3–1 g/m2 i.v. every 2–4 weeks; Ciclosporine A 5 mg/kg/d for 6 days then 2,5–3 mg/kg/d (titration to 100–200 ng/ml blood level); Mycophenolate-mofetil 1000–2000 mg/d; MTX 5–25 mg/week) [22–24]. In short-course treatments (Table 1) (e.g., IVIG, dexamethasone, anti-D, rituximab, Splx), response was defined as an elevation of plc ≥ 30 x 109/L with at least doubling of the baseline value within their individual agent/intervention time to peak response [32]. In patients under continuous treatments (Table 2), response criteria were a sustained elevation of plc ≥ 30 x 109/L with at least doubling of the baseline value and compensated primary hemostasis during treatment observation. Sustained remission was defined as plc ≥ 100 x 109/L without the requirement of further ITP therapy during at least 3 months of further observation (mean 25, months/range 3–108 months). Prior to assessment, all data has been fully anonymized. This study was approved by the institutional ethics review board (EA2/058112) of the Charité, Universitätsmedizin Berlin.\n\n10.1371/journal.pone.0198184.t001Table 1 Results of short-course treatments in patients with ITP during observation at our institution (n = 190).\nTherapy\tPatients (n)\tResponse\tNon-R\tTotal ARs\tCycles in R-patients (mean/range)\t\n\tTotal\tDocumented\tTotal R\tIntolerability/R\tSR/R\t\t\t\t\nIVIG\t133\t126\t94 (75%)\t-\t4/94\t32 (25%)\t18 (14%)\t3.1/1–25\t\nAnti-Da\t54\t52\t19 (37%)\t-\t-\t33 (63%)\t2 (4%)\t3.8/1–19\t\nDexa\t44\t42\t25 (60%)\t1/25\t-\t17 (40%)\t4 (10%)\t1.3/1–4\t\nRituxi\t4\t4\t1 (25%)\t-\t-\t3 (75%)\t-\t1.5/1–3\t\nSplx\t26\t25\t-\t-\t15 (60%)\t10 (40%)\t1 (4%)\t-\t\nR = response (elevation of platelets ≥ 30 x109/L and at least doubling of the baseline value within their known agent specific time to peak response [32]).\n\nSR = sustained remission (sustained platelet count ≥100 x 109/L without any further ITP therapy during at least 3 months of further observation).\n\nNon-R = non-responder (patients that did not show elevation of platelets ≥ 30 x109/L and at least doubling of the baseline value)\n\nARs = adverse reactions\n\nDocumented = patients with available follow-up data\n\nDexa = dexamethasone, IVIG = intravenous immunoglobuline, Rituxi = rituximab, Splx = splenectomy\n\na One patient with Splx prior to anti-D treatment\n\n10.1371/journal.pone.0198184.t002Table 2 Results of continuous treatments in patients with ITP during observation at our institution (n = 234).\nTherapy\tPatients (n)\tResponse\tNon-R\tTotal ARs\tTreatment time in months (mean/range)\t\n\tTotal\tDocumented\tTotal R\tIntolerability/R\tSR/R\t\t\t\t\nPred\t92\t88\t64 (73%)\t12/64\t8/64\t24 (27%)\t30 (34%)\t21.2 / 1–210\t\nAza\t14\t12\t7 (58%)\t1/7\t1/7\t5 (42%)\t4 (33%)\t13.6/0.5–48\t\nAza + Pred\t82\t78\t42 (54%)\t19/42\t1/42\t36 (46%)\t34 (44%)\t15/0.5–108\t\nRomip (+Preda)\t52\t45\t35 (78%)\t8/35\t-\t10 (22%)\t15 (33%)\t12,1/0.75–72\t\nEltromb\t64\t63\t45 (71%)\t14/45\t4/45\t18 (29%)\t22 (35%)\t15.6/0.5–96\t\nMTX (+Predb)\t5\t5\t2 (40%)\t-\t-\t3 (60%)\t-\t48.2/2–175\t\nCycl (+Predc)\t6\t6\t4 (66%)\t-\t-\t2 (33%)\t2 (33%)\t13.3/1.5–29\t\nCiclo (+Predd)\t12\t10\t1 (10%)\t-\t-\t9 (90%)\t1 (10%)\t5.8/0.75–18\t\nMMF (+Prede)\t15\t14\t7 (50%)\t3/7\t-\t7 (50%)\t6 (43%)\t15.7/ 1–60\t\nDapsone\t3\t3\t1 (33%)\t-\t-\t2 (66%)\t-\t41.3/ 2–120\t\nR = response (sustained platelet counts ≥30 x109/L with at least doubling the baseline value and absence of bleeding during observation).\n\nSR = sustained remission (sustained platelet counts ≥100 x 109/L without any further ITP therapy during at least 3 months of further observation).\n\nNon-R = non-responder (patients that did not show elevation of platelets ≥ 30 x109/L and at least doubling of the baseline value).\n\nARs = adverse reactions\n\nDocumented = patients with available follow-up data\n\nAza = azathioprine, Ciclo = ciclosporine, Cycl = cyclophosphamide, Eltromb = eltrombopag, MMF = mycophenolate- mofetil, MTX = methotrexate, Pred = prednisolone, Romip = romiplostim\n\na Five patients with concomitant prednisolone therapy;\n\nb four patients with concomitant prednisolone therapy;\n\nc five patients with concomitant prednisolone therapy;\n\nd one patient with concomitant prednisolone therapy;\n\ne twelve patients with concomitant prednisolone therapy\n\nResults\nPrior to consultation at our institution, 257 of 400 patients underwent treatment with therapies that were ineffective and/or intolerable due to side effects (Fig 1). The mean number of previous therapies was two (range 1–6). Prednisolone was the most frequent previously used drug (84%). The vast majority of these patients (88%) discontinued prednisolone due to inefficacy and/or intolerability including weight gain, hypertension, diabetes, osteoporosis, gastric ulceration or depression, resulting in a switch in therapy prior to initial consultation at our institution (Fig 1).\n\n10.1371/journal.pone.0198184.g001Fig 1 Patient and clinical characteristics.\nOne hundred (25%), including the two children, of the 400 patients did not require any therapeutic intervention during observation due to mild ITP and the absence of any bleeding and/or high bleeding risks. Of these 100 patients, 32 (39%) entered remission, 51 patients (61%) had persistent, but still mild ITP without the need for therapy, and long-term follow-up was absent in 17 patients (Fig 2).\n\n10.1371/journal.pone.0198184.g002Fig 2 Patients that just required controls due to mild ITP without any therapy during observation.\nThe remaining 300 patients received an average of two treatments (range 1–10) during observation at our institute.\n\nA total of 92 patients (23%) received prednisolone for at least one month (Table 2). Follow-up data were not available in four cases (4%). In the remaining 88 patients, 64 (73%) responded to this treatment. However, only eight (13%) of the responding patients entered sustained remission. Despite low-dose therapy (1–7.5 mg/d; Table 2), 12 (19%) patients developed intolerability during observation. Twenty-four patients (27%) did not respond to treatment.\n\nAzathioprine was used in 96 patients (24%), 82 of those had additional concomitant treatment with low-dose prednisolone (1–7.5 mg/d; Table 2). Six patients (6%) were not evaluated due to lack of follow-up data. In the remaining 90 patients, 49 patients (54%) responded to the treatment and 20 (41%) of those patients discontinued therapy due to adverse reactions, which included diverse gastrointestinal symptoms, hair loss, and drug fever. Two patients (2%) entered sustained remission without the need for further ITP therapy. Forty-one patients (46%) did not respond to the drug.\n\nForty-four patients (11%) were treated with dexamethasone at least once during observation (Table 1). Two patients (5%) were not evaluated due to lack of follow-up data. Of the remaining 42 patients, 25 (60%) responded to treatment (Table 1). Adverse reactions (headache, insomnia, mood disturbances, agitation, anxiety) were observed irregularly, and were tolerable in most cases. Seventeen patients (40%) did not respond to dexamethasone.\n\nOther immunosuppressive drugs including, cyclophosphamide, ciclosporin, mycophenolate- mofetil and rituximab showed response rates ranging from 10 to 66% (Tables 1 and 2). In addition, combination therapy with the aforementioned drugs and concomitant prednisolone therapy (≤ 7,5 mg/d) was used in some patients (Table 2). Adverse reactions observed during treatment with immunosuppressive drugs were largely in agreement with previously reported data [22–25].\n\nFifty-two patients (13%) were treated with romiplostim (Table 2). Seven patients (13%) were not evaluated due to lack of follow-up data. Of the remaining 45 patients, 35 patients (78%) responded to the drug. Treatment was discontinued in 8 (23%) of the responding patients due to adverse reactions [33, 34]. None of the patients treated with romiplostim entered sustained remission. A total of 10 patients (22%) did not respond to romiplostim. Eltrombopag was used in 64 patients (16%; Table 1). One patient (2%) was not evaluated due to lack of follow-up data. Of the remaining 63 patients, 45 patients (71%) responded to treatment (Table 2). Four of these patients (9%) entered sustained remission. Fourteen (31%) of the 45 responding patients discontinued treatment due to intolerable adverse reactions [33, 34]. Eighteen patients (29%) did not rspond to eltrombopag.\n\nIVIG was used in 133 patients (33%) on at least one occasion (Table 1). Seven patients (5%) were not evaluated due to lack of follow-up data. Of the remaining 126 patients, 94 (75%) responded to treatment, and none of the responding patients developed intolerable adverse reactions that contraindicated a re-treatment with IVIG. The observed adverse reactions were usually mild and related to headaches and rarely allergic reactions. Interestingly, four patients (4%) entered sustained remission following IVIG treatment (Table 1). Thirty-two patients (25%) did not respond to IVIG.\n\nTherapy with anti-D was selectively used in 54 Rh(D)-positive patients (14%) with refractory ITP (Table 1). Two patients (4%) were not evaluated due to lack of follow-up data. Nevertheless, of the remaining 52 patients, 19 (37%) responded to anti-D and two patients (4%) had adverse reactions (nausea, fever, headache) 24 h after administration that may be attributed to other origins. Hemolysis was not observed in a single patient. The lack of hemolysis might be explained by the subcutaneous administration [35–38]. Thirty-three patients (63%) did not respond to anti-D.\n\nSplx was performed in 20 patients (5%) prior to consultation at our institute. Of the remaining 380 non-splenectomized patients, 26 (7%) underwent Splx during the observation period (Table 1). One patient (1%) was not evaluated due to lack of follow-up data. Of the remaining 25 patients, 15 (60%) patients entered sustained remission after Splx. One non-responding patient developed postoperative abdominal pain and was diagnosed portal vein thrombosis (Table 1).\n\nDiscussion\nThe present study mainly focused on the efficacy and tolerability of each drug used in practice in the treatment of ITP rather than on patient outcome. While the latter question has been acknowledged by several studies [39–42], the former question has not yet been adequately addressed. The results presented in this study are based on patients treated by one physician who treats ITP patients since the 1980, not only on the basis of general recommendations, but also under individual consideration of each patient’s conditions. These included prior therapy, bleeding risk, plc, gender, age, weight, comorbidity, quality of life and patient’s preference. The importance of the latter point is reflected by the fact that many patients are well-informed on ITP. Based on the aforementioned criteria, at least 25% of patients did not require any treatment during observation (Fig 2). These patients did not have any significant bleeding or bleeding risk due to comorbidities, menstruation, activities/sports associated to injuries or invasive medical interventions. Their plc remained at levels compensating primary hemostasis (≥ 30 x 109/L) during observation. This observation is in agreement with previously published data [23].\n\nDrug-induced thrombocytopenia rather than ITP was suspected in 24 patients. At least nine of these patients (38%) entered sustained remission following discontinuation of the suspected drug.\n\nUnfortunately, many patients (55%) received steroids prior to consultation at our institute, even in cases where steroids should have been avoided, e.g., in patients with obesity, diabetes, and/or hypertension. Based on the aforementioned criteria, treatment with steroids was preferred as first-line therapy in only 31 of 143 patients that had not been treated for ITP prior to admission in our institute. Of these selected patients, 20 (65%) showed long-term beneficial effects that may have been solely attributed to steroids. However, these patients were a selected group of uncomplicated cases, e.g. young individuals with few or no comorbidities, with mild rather than severe ITP, no recognizable contraindication for treatment with steroids, and appeared to have a relatively low risk of developing intolerance. As the majority of such selected patients appeared to respond to steroids, we believe that this supports the notion of retaining steroids as a first-line therapy in ITP, however only in selected patients. In comparison, only (12%) of pretreated patients (27/257), still remained under steroid treatment upon initial presentation at our institute (Fig 1), and this treatment was discontinued in six of these cases during observation. Therefor the number of patients that continued treatment (10%) is primarily in agreement with previous reports [4].\n\nAnti-D was selectively used in 54 Rh(D)-positive patients with severe ITP that were largely refractory to previous medical therapy (Table 1). This may explain the relatively low response rate (37%) compared to unselected patient cohorts [4]. The reason for anti-D being not used in uncomplicated (naïve) patients is related to the fact that this therapeutic option is still not licensed for treatment of ITP in Germany.\n\nPrior to admission, 20 patients (5%) of the patient cohort were already splenectomized and four of them did not require any further medication. The other 16 patients required further therapy. During observation, only 26 (11%) of the remaining 284 non splenectomized and treated patients remained refractory to all available drugs, and ultimately underwent Splx. Fifteen of these patients (60%) entered sustained remission, and 10 (40%) required further treatments (Table 1). Of these 10 patients, seven patients responded to treatment with TPO-RA (six patients to romiplostim, one patient to eltrombopag), and the remaining patient responded to azathioprine and prednisolone (≤ 7,5 mg/d). Altogether, the therapies used in 26 splenectomized patients who required further therapy, were more effective than that used prior to Splx (Table 3).\n\n10.1371/journal.pone.0198184.t003Table 3 Therapies prior to and after splenectomy.\nTotal number of splenectomized patients (n = 46)\tPatients receiving treatment after Splx (n = 26)\t\nAbortive therapies prior to Splx\tPatients (n)\tTherapies after Splx\tPatients (n)\tResponse\tNon-R\t\nPred\t42\tPrednisolone\t5\t3 (60%)\t2 (40%)\t\nIVIG\t28\tIVIG\t12\t9 (75%)\t3 (25%)\t\nDexa\t9\tDexa\t2\t1 (50%)\t1 (50%)\t\nAnti-D\t12\tAnti-D\t1\t-\t1 (100%)\t\nRomip\t6\tRomip\t13\t10 (77%)\t3 (33%)\t\nEltromb\t7\tEltromb\t8\t4 (50%)\t4 (50%)\t\nRituxi\t4\tRituxi\t2\t-\t2 (100%)\t\nAza + Pred\t5\tAza + Pred\t6\t2 (33%)\t6 (66%)\t\nAza\t4\tAza\t1\t1 (100%)\t-\t\nCycl\t5\tCycl (+Preda)\t2\t1 (50%)\t1 (50%)\t\nCiclo\t3\tCiclo\t1\t1 (50%)\t-\t\nMMF\t4\tMMF (+Predb)\t2\t-\t2 (100%)\t\nDapsone\t1\tDapsone\t-\t-\t-\t\nResponse = short-course treatments: elevation of platelets ≥ 30 x109/L and at least doubling of the baseline value within their known agent specific time to peak response [32]. Continuous treatments: sustained platelet counts ≥30 x109/L with at least doubling the baseline value and absence of bleeding during observation.\n\nNon-R = non-responder (patients that did not show elevation of platelets ≥ 30 x109/L and at least doubling of the baseline value).\n\nAza = azathioprine, Ciclo = ciclosporin, Cycl = cyclophosphamide, Dexa = dexamethasone, Eltromb = eltrombopag, IVIG = intravenous immunoglobulin, MMF = mycophenolate- mofetil, MTX = methotrexate, Pred = prednisolone, Romip = romiplostim, Rituxi = rituximab, Splx = splenectomy.\n\na One patient with concomitant prednisolone therapy;\n\nb one patient with concomitant prednisolone therapy.\n\nThe finding that most therapeutic options were observed to become effective after Splx continues to emphasize the role of this therapeutic measure in the management of ITP as long as there is no specific treatment available. A similar conclusion has been drawn in previous studies [43, 44]. Most intriguingly, the efficacy of splenectomy appears to be independent of previous therapies and may therefore be considered as the ultima ratio therapy in refractory patients. Only two of the treated patients in this study remained refractory to all drugs used, even after splenectomy. One of these, a 53 year old female, who remained refractory to all drugs used (high-dose IVIG, platelet transfusion, eltrombopag, romiplostim, dexamethasone, dapsone and ultimately myeloablative dose cyclophosphamide 4 x 50 mg/kg/d) post-splenectomy. At first admission her blood count revealed only isolated thrombocytopenia and the blood marrow smear and bone marrow aspiration showed no abnormalities. This patient developed acute myeloid leukemia and died several weeks following treatment. The second refractory patient remained at risk of bleeding.\n\nThe results obtained using immunosuppressive agents were similar to those reported in previous studies [4]. Interestingly, similar response rates were observed in patients treated with azathioprine and treated with both azathioprine and low-dose (1–7.5 mg/d) prednisolone (50% vs. 51%). Other immunosuppressive drugs including cyclophosphamide, ciclosporin and mycophenolate-mofetil were only used in refractory patients. In most cases, the combination treatment of steroids and other immunosuppressive drugs was required to reduce steroid doses. A small group of 5 patients suffering from rheumatic diseases (3 patients with rheumatoid arthritis, 1 patient with systemic lupus erythematodes, 1 patient with psoriasis arthritis) was treated with MTX. None of these patients has been treated with MTX because of ITP. Nevertheless, a therapeutic effect of MTX on ITP, cannot be excluded. Two patients with concomitant prednisolone therapy met the response criteria during this therapy (Table 2).\n\nIVIG was administered to 133 patients, with 94 patients (75%) responding to treatment (Table 3). Thirty-two patients (25%) did not show an increase in plc as defined by the response criteria. In patients with bleeding, bleeding did not progress or was stopped after IVIG administration. We recently demonstrated that high dose IVIG may stop bleeding within 12 h after administration, independent of plc [45]. This phenomenon might be explained by an increased consumption of platelets for normalization of decompensated primary hemostasis in treated patients.\n\nThe TPO-RA, romiplostim and eltrombopag are increasingly used in the treatment of ITP. Previous studies have shown both drugs to be generally effective and safe in most ITP patients [9–12, 33, 34, 46–48]. However, in some cases, severe or dangerous adverse reactions including thromboembolic events, arthralgia, increased bone marrow fibrosis and myeloproliferative neoplasias may occur [9–12, 33, 34, 46–48]. Our results indicate that TPO-RAs are less effective and less tolerated (49–59%) than previously reported and may potentially result in an increased number of adverse reactions than previously reported [9–12, 33, 34, 46–48]. Adverse reactions occurred in 33% (romiplostim) and 35% (eltrombopag) of patients, respectively. Of the responding patients, eight (23%) discontinued romiplostim, and 14 (31%) discontinued eltrombopag due to intolerable adverse reactions. Nevertheless, these drugs have not only changed therapeutic treatment options in ITP, but also the outcome of treated patients. Previous studies have shown that approximately one-third of patients remained refractory to conventional treatment [49]. Currently, approximately <10% of patients may remain refractory to treatment [50, 51] and death may occur only in isolated cases [52]. In addition, the use of immunosuppressive drugs can nowadays rarely be justified.\n\nFinally, independent of Splx, 18 patients (6%) entered sustained remission (plc ≥100 x 109/L) due to treatment with various drugs (Tables 1 and 2). It remains unknown whether this phenomenon can only be attributed to the applied drugs mentioned in this study.\n\nConclusions\nAlthough only isolated patients may remain refractory to the currently available treatment options in ITP, there are many aspects that remain evident for the need of alternative drugs including specificity, safety, efficacy, predictability, and costs. In addition, we and others [13, 14, 27] agree with guidelines as a source of basic information, but individualized treatment is needed in many cases.\n\nLimitations of study\nAs the Dataset, collected retrospectively, does not contain uniquely all parameters for each patient, we prefered to conduct only descriptive instead of inferential statistics. Our retrospective study represents the treatment results in clinical practice. Thus, there was no possibility of monitoring platelet counts at prespecified standardized moments as in prospective trials. Moreover, the time to response is variable and cannot be predicted. It must be emphasized that not all adverse reactions were excluded, e.g. bone marrow fibrosis. In addition, a systemic screening for portal vein thrombosis by ultrasound or CT-scan after Splx was not performed. Furthermore our study presents data collected over a period of 20 years. During this period, therapeutic options as well as treatment recommendations have changed.\n\nInitially, most patients appeared to have isolated ITP. During observation, at least 57% (n = 227) of our patients exhibited other abnormalities e.g., DAT positivity, antibody deficiency, malignancies, or other diseases and abnormalities, Based on our experiences [53], the common classification into a primary and a secondary disease is not certain and variable in many cases. Moreover, the ITP itself might be responsible for the development of associated diseases at least in some cases. This is confirmed by the matter of fact that the manifestation of ITP precedes the manifestation of the associated diseases in some patients. Thus the question which disease is the primary one remains vague.\n\nSupporting information\nS1 File Dataset.\n(XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Whipple A.O . Splenectomy as a therapeutic measure in thrombocytopenic purpura haemorhagica . Surgery, Gynecology & Obstetrics . 1926 ; 42 : 329 –341 .\n2 Wintrobe MM , Cartwright GE , Palmer JG , Kuhns WJ , Samuels LT . Effect of corticotrophin and cortisone on the blood in various disorders in man . AMA Arch Intern Med . 1951 ; 88 : 310 –36 . 14856459 \n3 Burns CM . The History of Cortisone Discovery and Development . Rheum Dis Clin North Am . 2016 ; 42 : 1 –14 . doi: 10.1016/j.rdc.2015.08.001 \n26611547 \n4 Godeau B , Provan D , Bussel J . Immune thrombocytopenic purpura in adults . Curr Opin Hematol . 2007 ; 14 : 535 –56 . doi: 10.1097/MOH.0b013e3282b9748f \n17934364 \n5 Imbach P , Barandun S , d'Apuzzo V , Baumgartner C , Hirt A , Morell A \net al\nHigh-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood . Lancet . 1981 ; 1 : 1228 –31 . 6112565 \n6 Imbach P , Barandun S , Baumgartner C , Hirt A , Hofer F , Wagner HP . High-dose intravenous gammaglobulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood . Helv Paediatr Acta . 1981 ; 36 : 81 –6 . 6785258 \n7 Salama A , Mueller-Eckhardt C , Kiefel V . Effect of intravenous immunoglobulin in immune thrombocytopenia . Lancet . 1983 ; 2 : 193 –5 . 6135031 \n8 Saleh MN , Gutheil J , Moore , Bunch PW , Butler J , Kunkel L \net al\nA pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia . Semin Oncol . 2000 ; 27 : 99 –103 . 11226008 \n9 Cheng G , Saleh MN , Marcher C , Vasey S , Mayer B , Aivado M \net al\nEltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study . Lancet . 2011 ; 377 : 393 –402 . doi: 10.1016/S0140-6736(10)60959-2 \n20739054 \n10 Saleh MN , Bussel JB , Cheng G , Meyer O , Bailey CK , Arning M \net al\nEXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study . Blood . 2013 ; 121 : 537 –45 . doi: 10.1182/blood-2012-04-425512 \n23169778 \n11 Kuter DJ , Bussel JB , Lyons RM , Pullarkat V , Gernsheimer TB , Senecal FM \net al\nEfficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial . Lancet . 2008 ; 371 : 395 –403 . doi: 10.1016/S0140-6736(08)60203-2 \n18242413 \n12 Kuter DJ , Rummel M , Boccia R , Macik BG , Pabinger I , Selleslag D \net al\nRomiplostim or standard of care in patients with immune thrombocytopenia . N Engl J Med . 2010 ; 363 : 1889 –99 . doi: 10.1056/NEJMoa1002625 \n21067381 \n13 Salama A . Emerging drugs for immune thrombocytopenia (ITP) . Expert Opin Emerg Drugs . 2017 ; 22 : 27 –38 . doi: 10.1080/14728214.2017.1294158 \n28253829 \n14 Cuker A , Neunert CE . How I treat refractory immune thrombocytopenia . Blood . 2016 ; 128 : 1547 –54 . doi: 10.1182/blood-2016-03-603365 \n27053529 \n15 Provan D , Newland AC . Current Management of Primary Immune Thrombocytopenia . Adv Ther . 2015 ; 32 : 875 –87 . doi: 10.1007/s12325-015-0251-z \n26499177 \n16 Michel M , Suzan F , Adoue D , Bordessoule D , Marolleau JP , Viallard JF \net al\nManagement of immune thrombocytopenia in adults: a population-based analysis of the French hospital discharge database from 2009 to 2012 . Br J Haematol . 2015 ; 170 : 218 –22 . doi: 10.1111/bjh.13415 \n25824587 \n17 Matzdorff AC , Arnold G , Salama A , Ostermann H , Eberle S , Hummler S . Advances in ITP—therapy and quality of life—a patient survey . PLoS One . 2011 ; 6 : e27350 \ndoi: 10.1371/journal.pone.0027350 \n22096556 \n18 Salama A . Current treatment options for primary immune thrombocytopenia . Expert Rev Hematol . 2011 ; 4 : 107 –18 . doi: 10.1586/ehm.10.76 \n21322783 \n19 Weide R , Feiten S , Friesenhahn V , Heymanns J , Kleboth K , Thomalla J \net al\nOutpatient Management of Patients with Immune Thrombocytopenia (ITP) by Hematologists 1995–2014 . Oncol Res Treat. 2016 ; 39 : 41 –4 .\n20 Choi PY , Gordon JE , Harvey M , Chong BH . Presentation and outcome of idiopathic thrombocytopenic purpura in a single Australian centre . Intern Med J . 2012 ; 42 : 841 –5 . doi: 10.1111/j.1445-5994.2012.02740.x \n22805691 \n21 Chouhan JD , Herrington JD . Treatment options for chronic refractory idiopathic thrombocytopenic purpura in adults: focus on romiplostim and eltrombopag . Pharmacotherapy . 2010 ; 30 : 666 –83 . doi: 10.1592/phco.30.7.666 \n20575632 \n22 Vesely SK , Perdue JJ , Rizvi MA , Terrell DR , George JN . Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review . Ann Intern Med . 2004 ; 140 : 112 –20 . 14734334 \n23 Provan D , Stasi R , Newland AC , Blanchette VS , Bolton-Maggs P , Bussel JB \net al\nInternational consensus report on the investigation and management of primary immune thrombocytopenia . Blood . 2010 ; 115 : 168 –186 . doi: 10.1182/blood-2009-06-225565 \n19846889 \n24 Neunert C , Lim W , Crowther M , Cohen A , Solberg L Jr, Crowther MA ; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia . Blood . 2011 ; 117 : 4190 –4207 . doi: 10.1182/blood-2010-08-302984 \n21325604 \n25 Matzdorff A , Eberl W , Giagounidis A , Imbach P , Pabinger I , Wörmann B . Immune thrombocytopenia—onkopedic guidelines update: recommendations of a joint working group of the DGHO, ÖGHO, SGH + SSH and GPOH . Oncol Res Treat . 2010 ; 37 : 6 –25 .\n26 Lozano ML , Revilla N , Gonzalez-Lopez TJ , Novelli S , González-Porras JR , Sánchez-Gonzalez B et al. Real-life management of primary immune thrombocytopenia (ITP) in adult patients and adherence to practice guidelines . Ann Hematol . 2016 ; 95 : 1089 –98 . doi: 10.1007/s00277-016-2665-3 \n27098812 \n27 Ghanima W , Godeau B , Cines DB , Bussel JB . How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment . Blood . 2012 ; 120 : 960 –9 . doi: 10.1182/blood-2011-12-309153 \n22740443 \n28 Rodeghiero F , Besalduch J , Michel M , Provan D , Grotzinger K , Thompson G . Treatment practices in adults with chronic immune thrombocytopenia—a European perspective . Eur J Haematol . 2010 ; 84 : 160 –8 . doi: 10.1111/j.1600-0609.2009.01361.x \n19845743 \n29 Witmer CM , Lambert MP , O'Brien SH , Neunert C . Multicenter Cohort Study Comparing U.S. Management of Inpatient Pediatric Immune Thrombocytopenia to Current Treatment Guidelines . Pediatr Blood Cancer . 2016 ; 63 : 1227 –31 . doi: 10.1002/pbc.25961 \n26929009 \n30 Kühne T , Berchtold W , Tran VB , Tran VB , Imbach P . Ethnicity and environment may affect the phenotype of immune thrombocytopenic purpura in children . Pediatr Res . 2000 ; 48 : 374 –9 . doi: 10.1203/00006450-200009000-00019 \n10960506 \n31 Lee LH , Caguioa P , Chin NS , Chiou TJ , Lee JW , Miyakawa Y \net al\nChronic adult primary immune thrombocytopenia (ITP) in the Asia-Pacific region . Int J Hematol . 2011 ; 94 : 142 –9 . doi: 10.1007/s12185-011-0894-8 \n21766185 \n32 Rodeghiero F , Stasi R , Gernsheimer T , Michel M , Provan D , Arnold \net al\nStandardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adultsand children: report from an international working group . Blood . 2009 ; 113 : 2386 –93 . doi: 10.1182/blood-2008-07-162503 \n19005182 \n33 Depré F , Aboud N , Ringel F , Salama A . Thrombopoietin Receptor Agonists Are Often Ineffective in Immune Thrombocytopenia and/or Cause Adverse Reactions: Results from One Hand . Transfus Med Hemother . 2016 ; 43 : 375 –379 . doi: 10.1159/000446195 \n27781025 \n34 Depré F , Aboud N , Mayer B , Salama A . Bidirectional inefficacy or intolerability of thrombopoietin receptor agonists: new data and a concise review . Blood Transfus . 2017 ; 25 : 1 –6 .\n35 Meyer O , Kiesewetter H , Hermsen M , Petriedes P , Rose M , Seibt H \net al\nReplacement of intravenous administration of anti-D by subcutaneous administration in patients with autoimmune thrombocytopenia . Pediatr Blood Cancer . 2006 ; 47 : 721 –2 . doi: 10.1002/pbc.21006 \n16933269 \n36 Meyer O , Kiesewetter H , Hermsen M , Salama A . Efficacy and safety of anti-D given by subcutaneous injection to patients with autoimmune thrombocytopenia . Eur J Haematol . 2004 ; 73 : 71 –2 . doi: 10.1111/j.1600-0609.2004.00244.x \n15182342 \n37 Kjaersgaard M , Edslev PW , Hasle H . Subcutaneous anti-D treatment of idiopathic thrombocytopenic purpura in children . Pediatr Blood Cancer . 2009 ; 53 : 1315 –7 . doi: 10.1002/pbc.22248 \n19722275 \n38 Scaradavou A , Woo B , Woloski BM , Cunningham-Rundles S , Ettinger LJ , Aledort LM \net al\nIntravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients . Blood . 1997 ; 89 : 2689 –700 . 9108386 \n39 Mahévas M , Gerfaud-Valentin M , Moulis G , Terriou L , Audia S , Guenin S \net al\nCharacteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia . Blood . 2016 ; 128 : 1625 –30 . doi: 10.1182/blood-2016-03-704734 \n27354722 \n40 Nørgaard M , Jensen AØ , Engebjerg MC , Farkas DK , Thomsen RW , Cha S \net al\nLong-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study . Blood . 2011 ; 117 : 3514 –20 . doi: 10.1182/blood-2010-10-312819 \n21263148 \n41 Stasi R , Stipa E , Masi M , Cecconi M , Scimò MT , Oliva F \net al\nLong-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura . Am J Med . 1995 ; 98 : 436 –42 . 7733121 \n42 Cuker A , Prak , Cines DB . Can immune thrombocytopenia be cured with medical therapy? \nSemin Thromb Hemost . 2015 ; 41 : 395 –404 . doi: 10.1055/s-0034-1544001 \n25793364 \n43 Vesely SK , Perdue JJ , Rizvi MA , Terrell DR , George JN . Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review . Ann Intern Med . 2004 ; 140 : 112 –20 . 14734334 \n44 Vianelli N , Palandri F , Polverelli N , Stasi R , Joelsson J , Johansson E \net al\nSplenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years . Haematologica . 2013 ; 98 : 875 –80 . doi: 10.3324/haematol.2012.075648 \n23144195 \n45 Mayer B , Depré F , Ringel F , Salama A . New aspects on the efficacy of high-dose intravenous immunoglobulins in patients with autoimmune thrombocytopenia . Vox Sang . 2017 ; 112 : 64 –69 . doi: 10.1111/vox.12467 \n28001314 \n46 Khellaff M , Michel M , Quittet P , Viallard JF , Alexis M , Roudot-Thoraval F \net al\nRomiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in aromiplostim compassionate-use program . Blood . 2011 ; 118 : 4338 –45 . doi: 10.1182/blood-2011-03-340166 \n21832276 \n47 Bussell JB , Buchanan GR , Nugent DJ , Gnarra DJ , Bomgaars LR , Blanchette VS \net al\nA randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia . Blood . 2011 ; 118 : 28 –36 . doi: 10.1182/blood-2010-10-313908 \n21502541 \n48 Kuter DJ , Bussel JB , Newland A , Baker RI , Lyons RM , Wasser J \net al\nLong-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy . Br J Haematol . 2013 ; 161 : 411 –23 . doi: 10.1111/bjh.12260 \n23432528 \n49 McMillan R . Therapy for Adults with Refractory Chronic Immune Thrombocytopenic Purpura . Ann Intern Med . 1997 ; 126 : 307 –314 \n9036803 \n50 Psaila B , Bussel JB . Refractory immune thrombocytopenic purpura: current strategies for investigation and management . Br J Haematol. \n2008 ; 143 : 16 –26 . doi: 10.1111/j.1365-2141.2008.07275.x \n18573111 \n51 George JN . Management of patients with refractory immune thrombocytopenic purpura . J Thromb Haemost . 2006 ; 4 : 1664 –72 . doi: 10.1111/j.1538-7836.2006.02013.x \n16879206 \n52 Portielje JE , Westendorp RG , Kluin-Nelemans HC , Brand A . Morbidity and mortality in adults with idiopathic thrombocytopenic purpura . Blood . 2001 ; 97 : 2549 –2554 . 11313240 \n53 Aboud N , Depré F , Salama A . Is Autoimmune Thrombocytopenia Itself the Primary Disease in the Presence of Second Diseases Data from a Long-Term Observation . Transfus Med Hemother . 2017 ;44 :23 –28 . doi: 10.1159/000449038 \n28275330\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "13(6)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine; D001565:Benzoates; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016572:Cyclosporine; D003622:Dapsone; D003907:Dexamethasone; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006834:Hydrazines; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D012074:Remission Induction; D012189:Retrospective Studies; D018029:Rho(D) Immune Globulin; D000069283:Rituximab; D013156:Splenectomy; D013926:Thrombopoietin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0198184",
"pmc": null,
"pmid": "29856800",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "25793364;22805691;22096556;26499177;28275330;24613966;22740443;28151387;11313240;19722275;19005182;17934364;16879206;21263148;14856459;28001314;28253829;9036803;7733121;16933269;6135031;25824587;21322783;21325604;6112565;18573111;19845743;26891217;23144195;10960506;27781025;21067381;9108386;14734334;26929009;27053529;20739054;21766185;18242413;6785258;20575632;11226008;27098812;21832276;23432528;26611547;21502541;23169778;19846889;27354722;15182342",
"title": "Efficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia: Results from a long-term observation in clinical practice.",
"title_normalized": "efficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia results from a long term observation in clinical practice"
} | [
{
"companynumb": "DE-BAUSCH-BL-2018-023742",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo retrospectively estimate the efficacy of various treatments used in men with metastatic penile cancer that progresses after first-line chemotherapy.\n\n\nMETHODS\nPatients were from a 30-patient cohort with stage TxN2-3M0 penile squamous cell carcinoma treated with neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy before planned lymphadenectomy. Nineteen patients (63.3%) had tumor progression or recurrence, and we evaluated the response to subsequent treatment and survival.\n\n\nRESULTS\nSeventeen had received ≥ 1 salvage therapies; their median survival from first treatment failure was 5.7 months (range, 1.4-30.3 months). Four patients underwent salvage surgery, all of whom experienced further disease progression within 2 months. Four patients received chemoradiotherapy, 1 with stable disease for 13.5 months and 3 with no apparent benefit. Two of 5 evaluable patients (40%) who had received bleomycin, methotrexate, and cisplatin had objective responses (1 complete, 1 partial) but 1 developed fatal pneumonitis. There were no other documented responses to systemic therapy. Median overall survival was 5.6 months for patients who had received a second cisplatin-based treatment at any time and 4.3 months for those who had not (P = .4).\n\n\nCONCLUSIONS\nPatients whose metastatic penile carcinoma progresses through or recurs after front-line cisplatin-based chemotherapy experience poor responses to the described salvage treatments, with a median overall survival time of <6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.",
"affiliations": "Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: jwang19@mdanderson.org.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.",
"authors": "Wang|Jennifer|J|;Pettaway|Curtis A|CA|;Pagliaro|Lance C|LC|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2014.12.049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "85(5)",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010412:Penile Neoplasms; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "1104-1110",
"pmc": null,
"pmid": "25819619",
"pubdate": "2015-05",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Treatment for Metastatic Penile Cancer After First-line Chemotherapy Failure: Analysis of Response and Survival Outcomes.",
"title_normalized": "treatment for metastatic penile cancer after first line chemotherapy failure analysis of response and survival outcomes"
} | [
{
"companynumb": "US-PFIZER INC-2018120348",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.",
"affiliations": "Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany claus.vogelmeier@med.uni-marburg.de.;Respiratory Pathophysiology, University Hospital of Pisa, Pisa, Italy.;Hospital Universitari de Bellvitge, University of Barcelona, and Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.;2nd Dept of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.;Moncton Respirology Clinic, Moncton, NB, Canada.;Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, Member of the Germany Center for Lung Research (DZL), Grosshansdorf, Germany.;insaf Respiratory Research Institute, Wiesbaden, Germany.;AstraZeneca, Barcelona, Spain.;AstraZeneca, Barcelona, Spain.;Almirall SA, Barcelona, Spain.",
"authors": "Vogelmeier|Claus|C|;Paggiaro|Pier Luigi|PL|;Dorca|Jordi|J|;Sliwinski|Pawel|P|;Mallet|Marcel|M|;Kirsten|Anne-Marie|AM|;Beier|Jutta|J|;Seoane|Beatriz|B|;Segarra|Rosa Maria|RM|;Leselbaum|Anne|A|",
"chemical_list": "D001993:Bronchodilator Agents; D000068297:Fluticasone-Salmeterol Drug Combination; D014326:Tropanes; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; C542859:aclidinium bromide; D000068759:Formoterol Fumarate",
"country": "England",
"delete": false,
"doi": "10.1183/13993003.00216-2016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "48(4)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000328:Adult; D000368:Aged; D001993:Bronchodilator Agents; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone; D000068297:Fluticasone-Salmeterol Drug Combination; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D015272:Pulmonary Medicine; D000068299:Salmeterol Xinafoate; D012907:Smoking; D013147:Spirometry; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D014326:Tropanes",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "1030-1039",
"pmc": null,
"pmid": "27492833",
"pubdate": "2016-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study.",
"title_normalized": "efficacy and safety of aclidinium formoterol versus salmeterol fluticasone a phase 3 copd study"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2018097575",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "FLUTICASONE PROPIONATE\\SALMETEROL XINAFOATE"
},
... |
{
"abstract": "OBJECTIVE\nTo use 3D pseudocontinuous arterial spin labeling (3D PCASL) and dynamic susceptibility contrast-enhanced (DSC) perfusion MRI to differentiate progressive disease from pseudoprogression in patients with glioblastoma (GBM).\n\n\nMETHODS\nThirty-two patients with GBM who developed progressively enhancing lesions within the radiation field following resection and chemoradiation were included in this retrospective, single-institution study. The updated modified RANO criteria were used to establish progressive disease or pseudoprogression. Following 3D PCASL and DSC MR imaging, perfusion parameter estimates of cerebral blood flow (ASL-nCBF and DSC-nrCBF) and cerebral blood volume (DSC-nrCBV) were calculated. Additionally, contrast enhanced volumes were measured. Mann-Whitney U tests were used to compare groups. Linear discriminant analysis (LDA) and area under receiver operator characteristic curve (AUC) analyses were used to evaluate performance of each perfusion parameter and to determine optimal cut-off points.\n\n\nRESULTS\nAll perfusion parameter measurements were higher in patients with progressive disease (mean, 95% CI ASL-nCBF 2.48, [2.03, 2.93]; DSC-nrCBF = 2.27, [1.85, 2.69]; DSC-nrCBV = 3.51, [2.37, 4.66]) compared to pseudoprogression (mean, 95% CI ASL-nCBF 0.99, [0.47, 1.52]; DSC-nrCBF = 1.05, [0.36, 1.74]; DSC-nCBV = 1.19, [0.34, 2.05]), and findings were significant at the p < 0.0125 level (p = 0.001, 0.003, 0.002; effect size: Cohen's d = 1.48, 1.27, and 0.92). Contrast enhanced volumes were not significantly different between groups (p > 0.447). All perfusion parameters demonstrated high AUC (0.954 for ASL-nCBF, 0.867 for DSC-nrCBF, and 0.891 for DSC-nrCBV), however, ASL-nCBF demonstrated the highest AUC and misclassified the fewest cases (N = 6). Lesions correctly classified by ASL but misclassified by DSC were located along the skull base or adjacent to large resection cavities with residual blood products, at areas of increased susceptibility.\n\n\nCONCLUSIONS\nBoth 3D PCASL and DSC perfusion MRI techniques have nearly equivalent performance for the differentiation of progressive disease from pseudoprogression in patients with GBM. However, 3D PCASL is less sensitive to susceptibility artifact and may allow for improved classification in select cases.",
"affiliations": "Department of Radiology, University of California, San Diego, La Jolla, CA, 92037, USA. pmanning@ucsd.edu.;Department of Radiology, University of California, San Diego, La Jolla, CA, 92037, USA.;Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, 92037, USA.;Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, 92037, USA.;Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, 92037, USA.;Department of Radiology, University of California, San Diego, La Jolla, CA, 92037, USA.;Department of Radiology, University of California, San Diego, La Jolla, CA, 92037, USA.;Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92037, USA.;Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, 92037, USA.;Department of Radiology, University of California, San Diego, La Jolla, CA, 92037, USA.",
"authors": "Manning|Paul|P|http://orcid.org/0000-0002-2947-3894;Daghighi|Shadi|S|;Rajaratnam|Matthew K|MK|;Parthiban|Sowmya|S|;Bahrami|Naeim|N|;Dale|Anders M|AM|;Bolar|Divya|D|;Piccioni|David E|DE|;McDonald|Carrie R|CR|;Farid|Nikdokht|N|",
"chemical_list": "D003287:Contrast Media; D013113:Spin Labels",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-020-03475-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "147(3)",
"journal": "Journal of neuro-oncology",
"keywords": "ASL; DSC; GBM; Pseudoprogression; mRANO",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D003287:Contrast Media; D005260:Female; D005909:Glioblastoma; D006801:Humans; D021621:Imaging, Three-Dimensional; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D012680:Sensitivity and Specificity; D013113:Spin Labels; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "681-690",
"pmc": null,
"pmid": "32239431",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Differentiation of progressive disease from pseudoprogression using 3D PCASL and DSC perfusion MRI in patients with glioblastoma.",
"title_normalized": "differentiation of progressive disease from pseudoprogression using 3d pcasl and dsc perfusion mri in patients with glioblastoma"
} | [
{
"companynumb": "US-009507513-2006USA007064",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "A fatality following the ingestion of ibuprofen is reported. Ibuprofen is a prototypical nonsteroidal anti-inflammatory drug widely prescribed as an analgesic, anti-inflammatory, and antipyretic agent. To date, there are few case reports of fatal overdose with ibuprofen, following ibuprofen self-poisoning or accidental overdose. We report the case of a 51-year-old man with medical history of psychiatric disease, who was brought to the emergency department by ambulance with a chief complaint of having taken large amounts of drugs in a suicide attempt.Multiple empty containers of medications (ibuprofen, meloxicam, celecoxib, risperidone, citalopram, ketorolac, bromazepam) were found at the scene. He died 4 hours after admission to the emergency department, despite vigorous supportive care. Toxicological analyses were performed using a gas chromatography/mass spectrometry technique. The estimated ibuprofen concentration in the plasma was 600 μg/mL; gastric content was 200 μg/mL for this compound. Our report describes results of the forensic investigation and discuss the review of the literature.",
"affiliations": "Institute of Legal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.",
"authors": "Lodise|Maria|M|;De-Giorgio|Fabio|F|;Rossi|Riccardo|R|;d'Aloja|Ernesto|E|;Fucci|Nadia|N|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0b013e318253d6ff",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "33(3)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001929:Brain Edema; D049429:Forensic Pathology; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D005766:Gastrointestinal Contents; D006801:Humans; D007052:Ibuprofen; D007668:Kidney; D008099:Liver; D008168:Lung; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D011654:Pulmonary Edema; D013405:Suicide",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "242-6",
"pmc": null,
"pmid": "22835967",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Acute Ibuprofen intoxication: report on a case and review of the literature.",
"title_normalized": "acute ibuprofen intoxication report on a case and review of the literature"
} | [
{
"companynumb": "IT-PFIZER INC-2012193156",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Bilateral retinoblastoma (Rb) treatment remains a challenge for ophthalmologists and pediatric oncologists despite new therapeutic strategies for eye preservation. The purpose of this work is to evaluate treatment outcomes in patients who underwent eye salvage treatment at a single-center prior to the chemotherapy in situ era.\n\n\n\nWe followed a cohort of 88 consecutive Rb patients diagnosed at Hospital Infantil de México between November 2000 and June 2014. Eye salvage treatment consisted of systemic chemotherapy plus focal therapy planned by a multidisciplinary team. Unresponsive tumors were treated with episcleral brachytherapy and external beam radiotherapy (EBRT).\n\n\n\nA total of 96 eyes underwent eye salvaging therapy. Seventy-eight eyes (81%) were salvaged. Seven patients (8%) required brachytherapy and 34 patients (39%) underwent EBRT. Thirty-three of 78 preserved eyes (42%) achieved normal visual acuity: 5/27 (20%) in radiated patients and 28/51 (61%) in nonradiated patients. Eight patients developed secondary primary malignancies; however, those treated with EBRT did not have a significantly increased risk when compared with nonirradiated patients (OR: 1.66; P = 0.492). The overall survival rate was 86% (95% CI, 76%-92%) after a mean follow-up of 10 years.\n\n\n\nEye preservation, long-term tumor control, and functional visual acuity could be maintained in many child and adolescent Rb survivors. Our data suggest that ocular radiotherapy can be used as consolidation treatment when other recently developed therapies with potentially fewer side effects are not available. Multidisciplinary management of Rb is mandatory to obtain cancer control during eye salvage treatment.",
"affiliations": "Department of Ophthalmology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.;Department of Oncology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.;Department of Radiation Oncology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.;Center for Economic Studies in Health, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.;Department of Ophthalmology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.",
"authors": "Del Carmen Bernal-Díaz|Zaira|Z|;Murillo-Maldonado|Marco A|MA|;Pérez-Villanueva|Heynar|H|;Reyes-López|Alfonso|A|;Ramírez-Ortiz|Marco A|MA|0000-0002-2994-502X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28625",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(10)",
"journal": "Pediatric blood & cancer",
"keywords": "chemotherapy; laser therapy; radiotherapy; retinoblastoma; salvage therapy; visual impairment",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D059248:Chemoradiotherapy; D002675:Child, Preschool; D005123:Eye; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008800:Mexico; D009918:Orbital Neoplasms; D059351:Organ Sparing Treatments; D011379:Prognosis; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D016879:Salvage Therapy; D014792:Visual Acuity",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28625",
"pmc": null,
"pmid": "32743978",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ocular preservation in patients with bilateral retinoblastoma before chemotherapy in situ era: A report from a Mexican Retinoblastoma Reference Hospital.",
"title_normalized": "ocular preservation in patients with bilateral retinoblastoma before chemotherapy in situ era a report from a mexican retinoblastoma reference hospital"
} | [
{
"companynumb": "US-PFIZER INC-2020420680",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND Pregnancy causes a physiological increase in renal blood flow and glomerular filtration rate, which leads to a transient increase in urinary protein excretion. Up to 300 mg/d proteinuria is known to occur in pregnancy due to physiological changes. Proteinuria of greater than 3 g/d is categorized as being within the nephrotic range, and the most common cause of nephrotic range proteinuria in the later stages of pregnancy is preeclampsia. Minimal change disease (MCD) as a cause of nephrotic syndrome is rare in pregnancy and is rarer still after abortion. Here, we report a patient who presented with nephrotic syndrome due to MCD after elective surgical abortion. CASE REPORT A 21-year-old woman presented with shortness of breath, worsening anasarca, abdominal distension, and weight gain 3 weeks after undergoing elective surgical abortion at 7 weeks of gestation. There was no hematuria and no past medical history or family history of kidney disease. Investigations revealed normal serum creatinine with hypoalbuminemia, dyslipidemia, nephrotic range proteinuria, and negative serology for autoimmune diseases. Renal biopsy showed podocyte effacement with normal glomeruli and intact tubulointerstitium, confirming the diagnosis of MCD. The patient was treated with steroids, antidiuretics, statins, and angiotensin receptor blockers. She responded well, showing symptomatic improvement and resolution of proteinuria, hypoalbuminemia, and dyslipidemia. She was gradually tapered off steroids during subsequent follow-up visits. CONCLUSIONS Only a single case of a patient presenting with acute renal failure and MCD after a missed abortion has been reported. To the best of our knowledge, this is the second case report of MCD after abortion and the first report of a patient with MCD without acute renal failure after elective termination of pregnancy.",
"affiliations": "Division of Nephrology, Maimonides Medical Center, Brooklyn, NY, USA.;Division of Nephrology, Maimonides Medical Center, Brooklyn, NY, USA.;Division of Nephrology, Maimonides Medical Center, Brooklyn, NY, USA.;Division of Nephrology, Maimonides Medical Center, Brooklyn, NY, USA.",
"authors": "Greenberg|Sheldon|S|;Jana|Kundan R|KR|;Janga|Kalyana C|KC|;Kumar|Kamlesh|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.930292",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33771965\n10.12659/AJCR.930292\n930292\nArticles\nMinimal Change Disease After Elective Surgical Abortion: A Case Report\nGreenberg Sheldon ABCDEF\nJana Kundan R. ABCDEF\nJanga Kalyana C. ABCDEF\nKumar Kamlesh B\nDivision of Nephrology, Maimonides Medical Center, Brooklyn, NY, U.S.A.\nCorresponding Author: Sheldon Greenberg, e-mail: sgreenberg@maimonidesmed.org\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n27 3 2021\n22 e930292-1e930292-5\n05 12 2020\n28 1 2021\n18 2 2021\n© Am J Case Rep, 2021\n2021\nThis work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 21-year-old\n\nFinal Diagnosis: Minimal change disease\n\nSymptoms: Anasarca • proteinuria\n\nMedication: —\n\nClinical Procedure: Abortion\n\nSpecialty: Nephrology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nPregnancy causes a physiological increase in renal blood flow and glomerular filtration rate, which leads to a transient increase in urinary protein excretion. Up to 300 mg/d proteinuria is known to occur in pregnancy due to physiological changes. Proteinuria of greater than 3 g/d is categorized as being within the nephrotic range, and the most common cause of nephrotic range proteinuria in the later stages of pregnancy is preeclampsia. Minimal change disease (MCD) as a cause of nephrotic syndrome is rare in pregnancy and is rarer still after abortion. Here, we report a patient who presented with nephrotic syndrome due to MCD after elective surgical abortion.\n\nCase Report:\n\nA 21-year-old woman presented with shortness of breath, worsening anasarca, abdominal distension, and weight gain 3 weeks after undergoing elective surgical abortion at 7 weeks of gestation. There was no hematuria and no past medical history or family history of kidney disease. Investigations revealed normal serum creatinine with hypoalbuminemia, dyslipidemia, nephrotic range proteinuria, and negative serology for autoimmune diseases. Renal biopsy showed podocyte effacement with normal glomeruli and intact tubulointerstitium, confirming the diagnosis of MCD. The patient was treated with steroids, antidiuretics, statins, and angiotensin receptor blockers. She responded well, showing symptomatic improvement and resolution of proteinuria, hypoalbuminemia, and dyslipidemia. She was gradually tapered off steroids during subsequent follow-up visits.\n\nConclusions:\n\nOnly a single case of a patient presenting with acute renal failure and MCD after a missed abortion has been reported. To the best of our knowledge, this is the second case report of MCD after abortion and the first report of a patient with MCD without acute renal failure after elective termination of pregnancy.\n\nKeywords:\n\nAbortion, Induced\nNephrosis, Lipoid\nNephrotic Syndrome\n==== Body\nBackground\n\nA normal range proteinuria of up to 300 mg/d is known to occur in pregnancy, and it principally consists of tubular and glomerular protein [1]. Nephrotic syndrome is defined as proteinuria of more than 3 g/d with hypoalbuminemia and is often associated with edema and hypercholesterolemia. The incidence of nephrotic syndrome in pregnancy is 0.012–0.025% [2]. The most common cause of nephrotic range proteinuria in pregnancy after 20 weeks of gestational age is preeclampsia. Proteinuria before 20 weeks of gestation is usually suggestive of an underlying renal disease [3].\n\nThere have been very few reports of patients with minimal change disease (MCD) as a cause of nephrotic syndrome during pregnancy. The literature contains only a single case report of MCD with acute renal failure in a patient with a missed abortion [4]. In the current case report, we describe a patient who presented with anasarca after undergoing elective surgical abortion at 7 weeks of gestation and was found to have nephrotic syndrome due to MCD on renal biopsy.\n\nCase Report\n\nA 21-year-old woman presented with complaints of worsening anasarca for the past 3 weeks. She had undergone a surgical abortion 3 weeks before for nonmedical social reasons. She noticed bilateral lower extremity edema 3 days after the abortion. The edema progressively worsened during the following weeks, and she developed periorbital edema, sacral edema, abdominal distension, and shortness of breath. The patient also stated that she gained 25 kg in the last 3 weeks. She denied fever, cough, chest pain, nausea, vomiting, abdominal pain, or any urinary symptoms. She had no significant past medical history or family history. This pregnancy was her fourth. Obstetric history was significant for complete spontaneous abortion in her first pregnancy at 6 weeks gestational age. Subsequently, the patient had 2 healthy children, now aged 2.5 years and 1 year, through normal vaginal delivery without any complications. Urinary analysis during her third pregnancy showed no proteinuria, with serum albumin of 4.3 g/dL. During her fourth pregnancy, the patient elected to undergo a surgical abortion at 7 weeks 3 days gestational age. She had an albumin of 3.4 g/dL and serum creatinine of 0.7 mg/dL at the time of abortion (Table 1). Elective termination of pregnancy was performed by suction dilatation and curettage under aseptic conditions. Minimal bleeding was noted, and the patient tolerated the procedure well. She obtained adequate pain control with single dose of intramuscular ketorolac. She was discharged on ciprofloxacin 500 mg for 3 days. Three weeks later she presented to the hospital with anasarca as the chief concern.\n\nAt presentation, her vitals were normal with a blood pressure of 114/73 mmHg. On examination, the patient appeared well and was in no apparent distress. She had anasarca with peri-orbital edema, sacral edema, bilateral lower extremity edema, and abdominal wall distension with prominent striae. There was no abdominal fluid wave. Her lungs were clear and heart sounds were normal. Laboratory tests were significant for an albumin of 1.6 g/dL, cholesterol of 452 mg/dL, triglycerides of 345 mg/dL, and low-density lipoprotein of 292 mg/dL. Urinalysis demonstrated 6 g/d of protein with no white blood cells or red blood cells (Table 1). Serology workup, including double-stranded DNA, complement levels, anti-glomerular basement membrane antibody, antineutrophil cytoplasmic antibodies (c-ANCA, p-ANCA, and atypical ANCA), and rheumatoid factor, was negative. Serology for HIV, hepatitis B virus, and hepatitis C virus was also negative. A renal biopsy was performed, and no changes were found on light microscopy (Figure 1) or direct immunofluorescence. However, the biopsy revealed greater than 70% visceral epithelial foot process effacement with segmental microvillous transformation (Figure 2). These findings were consistent with a diagnosis of MCD.\n\nThe patient was started on 50 mg prednisone once daily, 20 mg furosemide once daily, losartan 25 mg once daily, and atorvastatin 80 mg once daily. Furosemide was discontinued 4 weeks later and steroid taper was started after 12 weeks. At 12 weeks follow-up, the patient had lost more than 31.8 kg and her urine protein had decreased to 30 mg/d from the initial 6 g/d. Anasarca, lower extremity swelling, and dyslipidemia also resolved, and the patient’s albumin improved from 1.5 to 4.1 g/dL. The patient was eventually tapered off steroids after 16 weeks and remained on losartan and statin.\n\nDiscussion\n\nMCD accounts for 15–25% of all adult-onset nephrotic syndrome [5]. The majority of cases with MCD are idiopathic. Secondary causes include drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), hematologic or solid malignancies, infections, and renal or systemic diseases [6,7]. MCD in pregnancy is especially rare, with only a few cases being reported to date. MCD associated with abortion is rarer still, with only a single case having been reported. In that case, the patient experienced a missed abortion at 8 weeks of gestation and also presented with acute renal failure. Renal biopsy showed normal histology on light microscopy with foot process effacement on electron microscopy [4].\n\nOur patient developed symptoms after elective termination of pregnancy by dilatation and curettage at 7 weeks 3 days of gestational age. She noticed bilateral lower extremity edema 3 days after the abortion, which progressed to anasarca with periorbital and sacral edema over the next 3 weeks. Renal biopsy confirmed isolated MCD. The patient also responded well to steroids, with proteinuria decreasing from 6 g to 80 mg in 4 weeks and dropping to 30 mg at 16 weeks. This pregnancy was the patient’s fourth in 4 years. Her first pregnancy was a spontaneous abortion due to unknown cause and the next 2 pregnancies ended with normal vaginal deliveries without any complications. The patient had no similar symptoms in her previous pregnancies, with albumin of 4.3 g/dL in her third pregnancy. She had no history of proteinuria or preeclampsia. Her albumin was 3.4 g/dL at the time of abortion of her fourth pregnancy.\n\nThe pathogenesis of MCD remains unknown, but T-cell-mediated cytokine release and upregulation of proteins that disrupt the integrity of podocytes have been proposed as major contributors [8]. Disorder of T lymphocytes in a case of missed abortion was thought to have precipitated MCD in the previously reported case [4]. During pregnancy there is Th2 polarization of immunity signifying a suppression of Th1-mediated immunity contributing to maternal tolerance of the fetus. A few studies have proposed MCD to be a Th2-mediated disease [9]. Although MCD did not manifest during our patient’s previous pregnancies, surgical abortion could have led to an exaggerated immune response leading to increased proinflammatory cytokines and subsequent podocyte injury. The favorable response to steroids and immunosuppressants points to a role for the immune system in this pathogenesis [10].\n\nOur patient received a single intramuscular dose of ketorolac for pain control. NSAIDs have been reported to cause MCD along with acute interstitial nephritis/acute tubular necrosis. A few studies have also reported isolated MCD due to NSAIDs. Fenoprofen, naproxen, and selective cyclooxygenase 2 inhibitors such as celecoxib have been implicated in the causation of nephrotic syndrome due to MCD [11,12]. It has been reasoned that NSAID-induced conversion of arachidonic acid to leukotrienes leads to activation of T cells. These activated T cells release cytokines that cause podocyte injury and increased glomerular permeability [13]. However, higher risk of nephrotic range proteinuria due to conventional NSAIDs occurs with a current use of more than 2 weeks [14]. Although our patient was given ketorolac, it was only a single intramuscular dose and renal biopsy showed no tubulointerstitial changes. Therefore, it is unlikely that MCD in our patient was due to NSAID use. NSAID-induced nephrotic syndrome has excellent remission with discontinuation of offending agent, which did not happen in our patient [15,16].\n\nSteroids form the first line of treatment for MCD. Although there is variability in the response to steroids and the course of the disease, studies have shown up to 75–90% responsiveness at a median of 10–13 weeks [17,18]. The patient in our case report showed excellent response to steroids. Her proteinuria decreased to normal levels with 4 weeks of steroid therapy and remained in remission. Steroids were tapered down after 12 weeks.\n\nConclusions\n\nThe role of immunological changes in the pathogenesis of MCD needs further investigation to elucidate the factors involved, especially in pregnancy and abortion. Our patient developed symptoms and nephrotic range proteinuria after undergoing abortion, with abrupt development of hypoalbuminemia. Although there is no conclusive evidence of causation, it is imperative to be mindful of a possible relationship between abortion and MCD. Renal biopsy should be performed in patients such as ours to institute timely treatment and thereby prevent the complications of prolonged proteinuria due to this disease.\n\nFigure 1. Light microscopy showing normal glomeruli and intact tubulointerstitium, ruling out interstitial disease.\n\nFigure 2. Electron microscopy showing podocyte effacement (red arrow) and swollen endothelial cells (blue stars) confirming minimal change disease.\n\nTable 1. Laboratory values of the patient at admission and at follow-up.\n\n\t\tAt the time of abortion\tAt admission\t1-week follow-Up\t4-week follow-up\t12-week follow-up\t\n\tWeight, kg\t76.7\t100.7\t104.3\t81.6\t70.3\t\nTotal protein, g/dL\t6\t3.5\t3.5\t4.9\t7.2\t\nAlbumin, g/dL\t3.4\t1.6\t1.5\t2.9\t4.1\t\nRenal indices\tCreatinine, mg/dL\t0.7\t0.7\t0.7\t0.7\t0.8\t\nBUN, mg/dL\t7\t9\t10\t13\t18\t\nUrine protein creatinine ratio\t\t6.0\t2\t0.08\t0.03\t\nSerology\tAnti-dsDNA, IU/mL\t\t<12\t\t\t\t\nAnti-GBM antibody, AI)\t\t<1.0\t\t\t\t\nC3, mg/dL\t\t132\t\t\t\t\nC4, mg/dL\t\t26\t\t\t\t\nLipid panel\tTotal cholesterol, mg/dL\t\t452\t\t243\t150\t\nTriglycerides, mg/dL\t\t345\t\t207\t110\t\nLDL, mg/dL\t\t292\t\t144\t75\t\nLiver function tests\tAST, IU/L\t24\t30\t\t\t\t\nALT, IU/L\t29\t23\t\t\t\t\nALP, IU/L\t76\t66\t\t\t\t\nBilirubin, mg/dL\t0.3\t0.2\t\t\t\t\nCoagulation profile\tPT, s\t\t10.3\t\t\t\t\nPTT, s\t\t34.1\t\t\t\t\nINR\t\t0.9\t\t\t\t\nPlatelet count/μL\t233 000\t259 000\t\t\t\t\nAI – antibody index; ALP – alkaline phosphatase; ALT – alanine transaminase; AST – aspartate transaminase; BUN – blood urea nitrogen; dsDNA – double-stranded DNA; GBM – glomerular basement membrane; INR – international normalized ratio; LDL – low-density lipoprotein; PT – prothrombin time; PTT – activated partial thromboplastin time.\n\nConflicts of interests\n\nNone.\n==== Refs\nReferences:\n\n1. ACOG Practice Bulletin No. 202: Gestational hypertension and preeclampsia Obstet Gynecol 2019 133 1 1\n2. Segarra-Medrano A Carnicer-Caceres C Arbos-Via MA Biological markers of nephrotic syndrome: A few steps forward in the long way Nefrologia 2012 32 5 558 72 23013941\n3. Gonzalez Suarez ML Kattah A Renal disorders in pregnancy: Core curriculum 2019 Am J Kidney Dis 2019 73 1 119 30 30122546\n4. Nishihara G Nakamoto M Yasunaga C Minimal-change nephrotic syndrome with acute renal failure associated with missed abortion Nephron 1998 80 2 234 36 9736828\n5. Vivarelli M Massella L Ruggiero B Minimal change disease Clin J Am Soc Nephrol 2017 12 2 332 45 27940460\n6. Kodner C Diagnosis and management of nephrotic syndrome in adults Am Fam Physician 2016 93 6 479 85 26977832\n7. Trachtman H Hogan J Radhakrishnan J Minimal change disease Gilbert SJ Weiner DE National Kidney Foundation Primer on Kidney Diseases Sixth Edition Philadelphia W.B. Saunders 2014 164 69\n8. Cara-Fuentes G Clapp WL Johnson RJ Pathogenesis of proteinuria in idiopathic minimal change disease: Molecular mechanisms Pediatr Nephrol 2016 31 12 2179 89 27384691\n9. Pan Q Wu J Tao J Role of basophils in the pathogenesis of minimal change nephrotic syndrome: A literature review Exp Ther Med 2014 8 4 1027 31 25187792\n10. Mathieson PW Immune dysregulation in minimal change nephropathy Nephrol Dial Transplant 2003 18 Suppl. 6 vi26 29 12953038\n11. Chen YH Tarng DC Profound urinary protein loss and acute renal failure caused by cyclooxygenase-2 inhibitor Chin J Physiol 2011 54 4 264 68 22129825\n12. Almansori M Kovithavongs T Qarni MU Cyclooxygenase-2 inhibitor-associated minimal-change disease Clin Nephrol 2005 63 5 381 84 15909598\n13. Vega J Goecke H Mendez GP Nephrotic syndrome and acute tubular necrosis due to meloxicam use Ren Fail 2012 34 10 1344 47 22963504\n14. Bakhriansyah M Souverein PC van den Hoogen MWF Risk of nephrotic syndrome for non-steroidal anti-inflammatory drug users Clin J Am Soc Nephrol 2019 14 9 1355 62 31416888\n15. Alper AB Jr Meleg-Smith S Krane NK Nephrotic syndrome and interstitial nephritis associated with celecoxib Am J Kidney Dis 2002 40 5 1086 90 12407655\n16. Merida E Praga M NSAIDs and nephrotic syndrome Clin J Am Soc Nephrol 2019 14 9 1280 82 31416889\n17. Szeto CC Lai FM Chow KM Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults Am J Kidney Dis 2015 65 5 710 18 25465164\n18. Canetta PA Radhakrishnan J The evidence-based approach to adult-onset idiopathic nephrotic syndrome Front Pediatr 2015 3 78 26442238\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007674:Kidney Diseases; D007678:Kidney Glomerulus; D009402:Nephrosis, Lipoid; D009404:Nephrotic Syndrome; D011247:Pregnancy; D011507:Proteinuria; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e930292",
"pmc": null,
"pmid": "33771965",
"pubdate": "2021-03-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26442238;30575675;27940460;22129825;31416888;15909598;9736828;25465164;12953038;30122546;27384691;25187792;23013941;22963504;31416889;12407655;26977832",
"title": "Minimal Change Disease After Elective Surgical Abortion: A Case Report.",
"title_normalized": "minimal change disease after elective surgical abortion a case report"
} | [
{
"companynumb": "US-ORGANON-O2106USA002071",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOSARTAN POTASSIUM"
},
"drugadditional": null... |
{
"abstract": "Sacubitril/valsartan has demonstrated its prognostic advantageousness over enalapril in patients with heart failure with a reduced ejection fraction. However, the optimal therapeutic strategy using sacubitril/valsartan in real-world practice, particularly among a Japanee cohort, remains uncertain. A 75-year-old man with systolic heart failure and chronic kidney disease was administered sacubitril/valsartan. Plasma B-type natriuretic peptide transiently increased, accompanied by an increase in the urine volume, which allowed us to terminate loop diuretics. The estimated glomerular filtration rate as well as heart failure symptom improved at the one-month follow-up. Sacubitril/valsartan might be a promising option to preserve the renal function and improve clinical outcomes when the dose of concomitant diuretics can be decreased, although further large-scale studies are warranted to validate our hypothesis.",
"affiliations": "The Second Department of Internal Medicine, University of Toyama, Japan.;The Second Department of Internal Medicine, University of Toyama, Japan.;The Second Department of Internal Medicine, University of Toyama, Japan.",
"authors": "Imamura|Teruhiko|T|;Hori|Masakazu|M|;Kinugawa|Koichiro|K|",
"chemical_list": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6713-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34470986\n10.2169/internalmedicine.6713-20\nCase Report\nOptimal Therapeutic Strategy Using Sacubitril/Valsartan in a Patient with Systolic Heart Failure and Chronic Kidney Disease - An Initial Case Report in Japan\nImamura Teruhiko 1\nHori Masakazu 1\nKinugawa Koichiro 1\n1 The Second Department of Internal Medicine, University of Toyama, Japan\nCorrespondence to Dr. Teruhiko Imamura, teimamu@med.u-toyama.ac.jp\n\n1 9 2021\n60 17 28072809\n13 11 2020\n27 12 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nSacubitril/valsartan has demonstrated its prognostic advantageousness over enalapril in patients with heart failure with a reduced ejection fraction. However, the optimal therapeutic strategy using sacubitril/valsartan in real-world practice, particularly among a Japanee cohort, remains uncertain. A 75-year-old man with systolic heart failure and chronic kidney disease was administered sacubitril/valsartan. Plasma B-type natriuretic peptide transiently increased, accompanied by an increase in the urine volume, which allowed us to terminate loop diuretics. The estimated glomerular filtration rate as well as heart failure symptom improved at the one-month follow-up. Sacubitril/valsartan might be a promising option to preserve the renal function and improve clinical outcomes when the dose of concomitant diuretics can be decreased, although further large-scale studies are warranted to validate our hypothesis.\n\nhemodynamics\nangiotensin receptor neprilysin inhibitor (ARNI)\nrenal function\n==== Body\npmcIntroduction\n\nThe clinical outcomes in patients with heart failure with a reduced ejection fraction have not yet been satisfactorily high despite the recent establishment of guideline-directed medical therapy, including beta-blockers, angiotensin-converting enzyme inhibitors, and mineralcorticoid antagonists (1).\n\nIn the PARADIGM-HF study (2), sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, has demonstrated its advantageousness over enalapril, an angiotensin-converting enzyme inhibitor, in preventing cardiovascular death or heart failure readmissions in patients with heart failure with reduced ejection fraction. Sacubitril/valsartan has been approved by the Japanese National Health Insurance Program since August 2020. However, the practical therapeutic strategy using sacubitril/valsartan and patients' detailed response in real-world daily practice remains to be elucidated.\n\nCare Report\n\nOn admission\n\nA 75-year-old man with medical histories of hypertension and paroxysmal supraventricular tachycardia was admitted to our institute complaining of dyspnea on effort (New York Heart Association class III) due to the dilated phase of hypertrophic cardiomyopathy, which was previously diagnosed by an endo-myocardial biopsy. He had twice been hospitalized previously due to a worsening heart failure for the past two years.\n\nMedication on admission was 2.5 mg/day of carvedilol, 2.5 mg/day of enalapril, and 4 mg/day of torasemide. He was intolerant to the further up-titration of carvedilol due to dizziness. His blood pressure was 141/92 mmHg and his heart rate was 86 bpm. His chest X-ray showed cardiomegaly and bilateral mild congestion. Saturation with 2 L of nasal cannula oxygenation support was 97%. Trans-thoracic echocardiography showed 64 mm of left ventricular end-diastolic diameter, 26% of left ventricular ejection fraction (calculated by the modified Simpson's method), and mild mitral regurgitation. Plasma B-type natriuretic peptide (BNP) was 159 pg/mL, NT-proBNP was 1,109 pg/mL, and estimated glomerular filtration ratio (eGFR) was 38.3 mL/min/1.73 m2.\n\nIn-hospital course\n\nFollowing the administration of 12.5 mg/day of spironolactone on day 2, his systolic blood pressure remained 120-130 mmHg, serum potassium level remained around 5.0 mEq/L, and eGFR remained around 40 mL/min/1.73 m2 (Figure). After 2 days following the termination of enalapril (day 4 and 5), we initiated 100 mg/day of sacubitril/valsartan for his refractory heart failure on day 6.\n\nFigure. Time course. After admission, we initiated 100 mg/day of sacubitril/valsartan to treat heart failure refractory to guideline-directed medical therapy. BNP: B-type natriuretic peptide, serum-K: serum potassium, sBP: systolic blood pressure, eGFR: estimated glomerular filtration rate, HR: heart rate, BW: body weight\n\nFollowing the initiation of sacubitril/valsartan\n\nHis systolic blood pressure slightly decreased down to 110-120 mmHg and serum potassium level remained around 5.0 mEq/L. The plasma level of BNP slightly increased from 168 pg/mL to 198 pg/mL transiently, whereas plasma level of NT-proBNP decreased from 978 pg/mL to 451 pg/mL. Given that daily urine volume relatively increased (no data are shown) and body weight decreased approximately 1 kg after 2 days, we terminated 4 mg/day of torasemide. He was discharged with an optimized heart failure symptom on day 10.\n\nPost-discharge course\n\nAt 30 days following the index discharge, the plasma level of NT-proBNP remained unchanged and BNP slightly decreased from 198 pg/mL to 80 pg/mL. Of note, eGFR improved from 39.8 to 46.7 mL/min/1.73 m2.\n\nDiscussion\n\nIndications for sacubitril/valsartan\n\nOur patient had worsening heart failure refractory to guideline-directed medical therapy (1). We confirmed the tolerability to enalapril beforehand. This would be a key to avoid unplanned withdrawal of sacubitril/valsartan, which might rather cause hemodynamic deterioration and an increase in the plasma NT-proBNP level, as observed in the enalapril arm of the PARADIGM-HF study (3).\n\nAppropriate patients selection\n\nGiven the sub-analysis of the PARADIGM-HF study (2), our patient might have a favorable profile for the sacubitril/valsartan therapy, i.e., New York Heart Association functional class <III and left ventricular ejection fraction <35%. However, the impact of sacubitril/valsartan on the Asian population remains controversial (2,4). We confirmed a relatively well preserved blood pressure and renal function to prevent adverse events before the start of sacubitril/valsartan administration.\n\nReaction to sacubitril/valsartan\n\nFollowing the administration of sacubitril/valsartan, the plasma BNP level increased slightly probably due to the inhibition of neprilysin, and plasma NT-proBNP level decreased significantly, indicating an improvement in heart failure. The plasma BNP level also decreased 30 days later, probably due to a further improvement in heart failure.\n\nThe blood pressure did not decrease considerably (within 10 mmHg), which would indicate a favorable clinical outcome (5). An immediate decrease in body weight would probably have been driven by the increased urine volume. Increased active BNP might have facilitated natriuresis as a visible acute effect of sacubitril/valsartan. As a result, we could terminate torasemide, which might have resulted in the observed improvement of the renal function (6).\n\nLong-term outcomes\n\nNatriuresis would be one of the visible acute effects of sacubitril/valsartan. We believe that a decrease in the dose of concomitant diuretics might have a potential to improve renal function. We demonstrated a similar finding in the meta-analysis of tolvaptan, a vasopressin type-2 receptor antagonist (7). Patients who achieved a decrease in the diuretics dose following the administration of tolvaptan tended to have a better long-term prognosis. To the best of our knowledge, this is the first case report of sacubitril/valsartan administration in Japan. Further large-scale observational studies are warranted to validate our proposed therapeutic strategy.\n\nWe continued to administer 100 mg/day of sacubitril/valsartan given relatively lower blood pressure. Given the results of PIONEER-HF study (8), dose up-titration might not necessarily be essential. Instead, we should avoid too much hypotension and unplanned termination of sacubitril/valsartan, which might cause a deterioration of the hemodynamics due to the acute the re-activation of neprilysin (3).\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\n\nJSPS KAKENHI: JP20K17143.\n==== Refs\n1. Tsutsui H , Isobe M , Ito H , et al . JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version. Circ J 83 : 2084-2184, 2019.31511439\n2. McMurray JJ , Packer M , Desai AS , et al . Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371 : 993-1004, 2014.25176015\n3. Myhre PL , Vaduganathan M , Claggett B , et al . B-Type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol 73 : 1264-1272, 2019.30846338\n4. Tsutsui H , Momomura S , Saito Y , et al . Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: rationale for and design of the randomized, double-blind PARALLEL-HF study. J Cardiol 70 : 225-231, 2017.28024961\n5. Bohm M , Young R , Jhund PS , et al . Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 38 : 1132-1143, 2017.28158398\n6. Vardeny O , Claggett B , Kachadourian J , et al . Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail 21 : 337-341, 2019.30741494\n7. Imamura T , Kinugawa K . Update of acute and long-term tolvaptan therapy. J Cardiol 73 : 102-107, 2019.30420105\n8. Velazquez EJ , Morrow DA , DeVore AD , et al . Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 380 : 539-548, 2019.30415601\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "angiotensin receptor neprilysin inhibitor (ARNI); hemodynamics; renal function",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure; D054143:Heart Failure, Systolic; D006801:Humans; D007564:Japan; D008297:Male; D015260:Neprilysin; D051436:Renal Insufficiency, Chronic; D013318:Stroke Volume; D013777:Tetrazoles; D016896:Treatment Outcome; D000068756:Valsartan",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2807-2809",
"pmc": null,
"pmid": "34470986",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30420105;30846338;30415601;28158398;30741494;28024961;25176015;31511439",
"title": "Optimal Therapeutic Strategy Using Sacubitril/Valsartan in a Patient with Systolic Heart Failure and Chronic Kidney Disease - An Initial Case Report in Japan.",
"title_normalized": "optimal therapeutic strategy using sacubitril valsartan in a patient with systolic heart failure and chronic kidney disease an initial case report in japan"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-314035",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drug... |
{
"abstract": "BACKGROUND\nManagement of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT).\n\n\nMETHODS\nInclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks.\n\n\nRESULTS\nSixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities.\n\n\nCONCLUSIONS\nWe conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results.",
"affiliations": "*Oncology Department, The Children's Hospital at Westmead, NSW †Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia.",
"authors": "Kalra|Manas|M|;Heath|John A|JA|;Kellie|Stewart J|SJ|;Dalla Pozza|Luciano|L|;Stevens|Michael M|MM|;Swamy|Shruti|S|;McCowage|Geoffrey B|GB|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077146:Irinotecan; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D002166:Camptothecin; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D019233:Retreatment; D012189:Retrospective Studies; D016879:Salvage Therapy",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e341-6",
"pmc": null,
"pmid": "26056795",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma.",
"title_normalized": "confirmation of bevacizumab activity and maintenance of efficacy in retreatment after subsequent relapse in pediatric low grade glioma"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-109163",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"dru... |
{
"abstract": "OBJECTIVE\nOpioid dependence remains the main type of illicit substance used in Malaysia, which has an estimated 187 771 opiate users. There are currently 333 active methadone maintenance treatment centres nationwide. Although methadone has proven to be an effective maintenance therapy, it has clinical concerns which can have an impact on its effectiveness and safety.\nA case series of seven patients from Malaysian private and public hospital settings who had an adverse reaction with methadone is discussed.\n\n\nCONCLUSIONS\nDespite methadone being an effective therapy for opioid dependence, there is a need for other alternative effective therapies, such as naltrexone, buprenorphine and the co-formulation of buprenorphine-naloxone, to be made available to physicians in both public and private sectors. There is need for individual treatment consideration to avoid adverse effects, drug-drug interactions, overdosing and in the presence of co-morbidities. An emphasis on safe storage of takeaway methadone is also needed. [George P, Vicknasingam B, Thurairajasingam S, Ramasamy P, Mohd Yusof H, Yasin MABM, Shah ZUBS. Methadone complications amongst opioid-dependent patients in Malaysia: A case series. Drug Alcohol Rev 2018;37:147-151].",
"affiliations": "School of Medicine, International Medical University, Kuala Lumpur, Malaysia.;Centre for Drug Research, Universiti Sains, George Town, Malaysia.;School of Medicine, Monash University, Subang Jaya, Malaysia.;Hospital Kuala Pilah, Kuala Pilah, Malaysia.;Hospital Permai, Johor Bahru, Malaysia.;School of Medicine, Monash University, Subang Jaya, Malaysia.;School of Medicine, International Medical University, Kuala Lumpur, Malaysia.",
"authors": "George|Philip|P|;Vicknasingam|Balasingam|B|;Thurairajasingam|Sivakumar|S|;Ramasamy|Parameswaran|P|;Mohd Yusof|Haslina|H|;Yasin|Mohd Azhar Bin Mohd|MABM|;Shah|Zia U Bahkt Sultan|ZUBS|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "Australia",
"delete": false,
"doi": "10.1111/dar.12456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-5236",
"issue": "37(1)",
"journal": "Drug and alcohol review",
"keywords": "adverse effect; interaction; methadone; methadone poisoning; opioid dependence",
"medline_ta": "Drug Alcohol Rev",
"mesh_terms": "D000328:Adult; D002675:Child, Preschool; D062787:Drug Overdose; D004487:Edema; D005260:Female; D006801:Humans; D008296:Malaysia; D008297:Male; D008691:Methadone; D009294:Narcotics; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011537:Pruritus",
"nlm_unique_id": "9015440",
"other_id": null,
"pages": "147-151",
"pmc": null,
"pmid": "27859761",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methadone complications amongst opioid-dependent patients in Malaysia: A case series.",
"title_normalized": "methadone complications amongst opioid dependent patients in malaysia a case series"
} | [
{
"companynumb": "MY-MYLANLABS-2018M1089530",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": "1",
... |
{
"abstract": "Vascular complications of severe acute pancreatitis are well known and largely described unlike non-occlusive mesenteric ischemia, which is a rare and potentially fatal complication. Non-occlusive mesenteric ischemia is an acute mesenteric ischemia without thrombotic occlusion of blood vessels, poorly described as a complication of acute pancreatitis.\n\n\n\nWe retrospectively reviewed a prospectively maintained registry of all pancreatic diseases referred to our center from 2013 to 2018, in order to determine the causes of early death. We identified three patients who died within 48 h after hospital admission from severe acute pancreatitis complicated by irreversible non-occlusive mesenteric ischemia. Their clinical presentation, management, and outcomes were herein reported.\n\n\n\nThree consecutive patients with severe acute pancreatitis developed non-occlusive mesenteric ischemia within the first 5 days after onset of symptoms and died 48 h after non-occlusive mesenteric ischemia diagnosis despite optimal intensive care management and surgery, giving a prevalence of 3/609 (0.5%). Symptoms were unspecific with consequently potential delayed diagnosis and management. High doses of norepinephrine required for hemodynamic support (n = 3) potentially leading to splanchnic vessels vasoconstriction, transient hypotension (n = 3), and previous severe ischemic cardiomyopathy (n = 1) could be involved as precipitating factors of non-occlusive mesenteric ischemia.\n\n\n\nNon-occlusive mesenteric ischemia can be a fatal complication of acute pancreatitis but is also challenging to diagnose. Priority is to reestablish a splanchno-mesenteric perfusion flow. Surgery should be offered in case of treatment failure or deterioration but is still under debate in early stage, to interrupt the vicious circle of intestinal hypoperfusion and ischemia.",
"affiliations": "Department of Gastroenterology, Hepatology and Digestive Oncology, Centre Hospitalier Universitaire de Dijon, 14 Rue Paul Gaffarel, 21000, Dijon, France.;Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Digestive Surgery, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Digestive Surgery, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Hepato-Gastroenterology, Saint-Pierre Hospital, Université Libre de Bruxelles, Rue aux Laines 105, 1000, Brussels, Belgium.;Department of Gastroenterology, Hepato-Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Department of Gastroenterology, Hepato-Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium. myriam.delhaye@erasme.ulb.ac.be.",
"authors": "Reichling|Cynthia|C|;Nobile|Leda|L|;Pezzullo|Martina|M|;Navez|Julie|J|;Bachir|Najla|N|;D'Haene|Nicky|N|;Maris|Calliope|C|;Musala|Carmen|C|;Fernandez Y Viesca|Michael|M|;Grimaldi|David|D|;Delhaye|Myriam|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-05835-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "65(4)",
"journal": "Digestive diseases and sciences",
"keywords": "Acute abdomen; Acute necrotizing pancreatitis; Fatal outcome; Non-occlusive mesenteric ischemia; Peritonitis; Second-look surgery",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000368:Aged; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D065666:Mesenteric Ischemia; D008875:Middle Aged; D010195:Pancreatitis; D011446:Prospective Studies; D012042:Registries; D012189:Retrospective Studies",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "1212-1222",
"pmc": null,
"pmid": "31529415",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23100216;17667501;16549646;16543793;28281168;15505289;11976865;16132892;29206674;27858375;8604831;25294021;12890994;18425546;12499910;29992520;11420490;4023241;1731388;929375;17079934;23296712;21741922;6030932;28838972;23885938;8604829;26820988;11877691;16398814;17079936;26962730;28794797;14716789;8844239;3962947;11336191;15159262",
"title": "Non-occlusive Mesenteric Ischemia as a Fatal Complication in Acute Pancreatitis: A Case Series.",
"title_normalized": "non occlusive mesenteric ischemia as a fatal complication in acute pancreatitis a case series"
} | [
{
"companynumb": "NVSC2020BE094488",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditional": nul... |
{
"abstract": "Subarachnoid hemorrhage is a devastating form of stroke with often detrimental outcomes for patients. Here we describe a patient with subarachnoid hemorrhage treated with nimodipine, which resulted in marked bradycardia with junctional atrioventricular heart block. Nimodipine is metabolized predominantly by the cytochrome P450 3A subfamily, and its use is often associated with adverse events, such as hypotension and bradycardia, which can be exacerbated by advanced age. Our patient had the CYP3A5*3/*3 genotype, possibly predisposing her to poor metabolism of this drug. Our case report demonstrates the potential for pharmacogenomics in patients with subarachnoid hemorrhage to help predict their response to nimodipine, minimize adverse drug reactions, and potentially individualize dosing to improve future clinical outcomes.",
"affiliations": "Mayo Clinic Alix School of Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.",
"authors": "James|Courtney L|CL|;Turnbull|Marion T|MT|;Freeman|William D|WD|0000-0003-2326-0633",
"chemical_list": "D000959:Antihypertensive Agents; D009553:Nimodipine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2019-0136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "21(6)",
"journal": "Pharmacogenomics",
"keywords": "cytochrome P450; nimodipine; pharmacogenomics; precision medicine; subarachnoid hemorrhage",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D001919:Bradycardia; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006801:Humans; D009553:Nimodipine; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "387-392",
"pmc": null,
"pmid": "32284009",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nimodipine-induced junctional bradycardia in an elderly patient with subarachnoid hemorrhage.",
"title_normalized": "nimodipine induced junctional bradycardia in an elderly patient with subarachnoid hemorrhage"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-245206",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIMODIPINE"
},
"drug... |
{
"abstract": "A 59-year-old woman was admitted to the hospital with a fever and rigors for 2 days. She was on chemotherapy (docetaxel, carboplatin, and trastuzumab) for her stage II invasive ductal carcinoma of the breast. Her physical exam was unremarkable except for the fever. The white blood cells were 21,200/mm(3) with 92% of neutrophils. ESR was 106 mm/h. An extensive infectious workup was negative. On day 6, while still febrile, the patient complained of a left-sided neck pain. She exhibited tenderness over the left carotid artery. A CT scan of the neck without intravenous contrast showed perivascular inflammation of the left common carotid artery, without evidence of a collection, arterial thrombosis, aneurysm, or dissection. The etiology of this finding was possibly chemotherapy related. It dramatically responded to oral prednisone. A repeat CT scan of the neck with IV contrast 2 weeks later showed a remarkable improvement. Drug reactions can simulate systemic inflammatory diseases and should always be considered in the diagnosing process.",
"affiliations": "Beth Israel Medical Center, New York, USA. Lazar@chpnet.org",
"authors": "Azar|Lama|L|;Fischer|Harry D|HD|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-009-1309-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "32(2)",
"journal": "Rheumatology international",
"keywords": null,
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002340:Carotid Artery Diseases; D017536:Carotid Artery, Common; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007249:Inflammation; D008875:Middle Aged; D019547:Neck Pain; D011859:Radiography; D014657:Vasculitis",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "457-9",
"pmc": null,
"pmid": "20091034",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15728007;15661731;11857321;11566713;10782793;12853590;17522249;15205600;11720456",
"title": "Perivascular carotid inflammation: an unusual case of carotidynia.",
"title_normalized": "perivascular carotid inflammation an unusual case of carotidynia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-110385",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "BACKGROUND\nMetformin is nowadays considered as first-line therapy in individuals with non-insulin dependent diabetes mellitus (NIDDM). Metformin-related lactic acidosis (MALA) occurs more frequently after inappropriate use especially in patients with acute kidney injury (AKI) or chronic kidney disease (CKD). Thus, its prescription in these patients is contraindicated, while the role of dialysis is under evaluation.\n\n\nMETHODS\nWe describe two cases of severe metformin-related lactic acidosis with underlying acute kidney injury, which were treated with dialysis.\n\n\nRESULTS\nIn both cases, lactic acidosis occurred on a background of acute decline in renal function, possibly due to drug accumulation. It is interesting that metformin was contraindicated in one case.\n\n\nCONCLUSIONS\nLactic acidosis is a rare but potentially fatal adverse effect of metformin, particularly in patients with AKI, which should always be considered in clinical practice. Dialysis seems to contribute significantly to the management of this life-threatening condition and the improvement in outcome.",
"affiliations": "Division of Nephrology, University Hospital of Alexandroupolis, Faculty of Medicine, Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Greece. vasdeve@yahoo.gr",
"authors": "Devetzis|Vassilios|V|;Passadakis|Ploumis|P|;Panagoutsos|Stelios|S|;Theodoridis|Marios|M|;Thodis|Elias|E|;Georgoulidou|Anastasia|A|;Vargemezis|Vassilis|V|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11255-010-9845-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-1623",
"issue": "43(4)",
"journal": "International urology and nephrology",
"keywords": null,
"medline_ta": "Int Urol Nephrol",
"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D000368:Aged; D000075202:Contraindications; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "0262521",
"other_id": null,
"pages": "1243-8",
"pmc": null,
"pmid": "20859683",
"pubdate": "2011-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12126190;19036140;18571361;9742977;16675650;631460;18095950;1955512;344119;5561472;16750454;15220268;16423187;12243370;2822788;8872955;18945920;2500402;15680458;7249508;1870755;433281;10372243;16415668;15252185;19433973;16437448;8923861;9771180;7623903;18817800;17974034;17331245;15127322;19487945;14638559;9175069;8569826;10839993;15312219;15047621;499320;16449278;9441244;11472468;7555503;7623902",
"title": "Metformin-related lactic acidosis in patients with acute kidney injury.",
"title_normalized": "metformin related lactic acidosis in patients with acute kidney injury"
} | [
{
"companynumb": "GR-RANBAXY-2012R1-57701",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": null,
... |
{
"abstract": "Dermatofibromas are benign, fibrohistiocytic, dermal tumors. Solitary dermatofibromas may be incidental findings, whereas multiple dermatofibromas may be associated with systemic conditions or previous therapies. Two women and one man with multiple dermatofibromas and an associated systemic condition, immunosuppression, or both, are described. Nine dermatofibromas developed in a woman with hypothyroidism, optic neuritis, and Arnold Chiari I malformation. Five dermatofibromas developed in a woman with breast cancer who had received several systemic antineoplastic therapies. Eleven dermatofibromas developed in a man with HIV whose systemic therapies included acyclovir, darunavir/cobicistat, dolutegravir, etravirine, and ritonavir. Conditions associated with multiple dermatofibromas include autoimmune diseases, cancer, chromosomal abnormalities, immunodeficiencies, metabolic disturbances, and altered physiologic states such as pregnancy. Medications received by patients with multiple dermatofibromas included immunosuppressive agents, psoriasis therapies, and antineoplastic drugs. Multiple dermatofibromas can be observed in patients with associated medical conditions, systemic therapies, or both. Therefore, in individuals presenting with multiple dermatofibromas, not only evaluation for associated disorders, but also review of prior and current drug therapies, should be considered.",
"affiliations": "Department of Internal Medicine, Scripps Mercy Hospital, San Diego, California. surgetbeatrous@gmail.com.",
"authors": "Beatrous|Surget V|SV|;Riahi|Ryan R|RR|;Grisoli|Stratton B|SB|;Cohen|Philip R|PR|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(9)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D001139:Arnold-Chiari Malformation; D001943:Breast Neoplasms; D005260:Female; D015658:HIV Infections; D018219:Histiocytoma, Benign Fibrous; D006801:Humans; D007037:Hypothyroidism; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009902:Optic Neuritis",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29469716",
"pubdate": "2017-09-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Associated conditions in patients with multiple dermatofibromas: Case reports and literature review.",
"title_normalized": "associated conditions in patients with multiple dermatofibromas case reports and literature review"
} | [
{
"companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2018-00041",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"dru... |
{
"abstract": "Patients with juvenile myoclonus epilepsy (JME) may experience uncontrolled seizures and challenges regarding adherence. Implementation of therapeutic drug monitoring (TDM) may contribute to individualization of the therapy with antiepileptic drugs (AEDs). The purpose of this study was to investigate how the treatment of patients with JME is monitored and to demonstrate pharmacokinetic variability within and between patients with a long-term TDM approach.\n\n\n\nRetrospective data from patients with JME from the TDM-database at Drammen Hospital and the National Center for Epilepsy in Norway (2007-2018) were included.\n\n\n\nData from 80 of 90 patients with JME using AEDs with TDM measurements was included (88%, 49/31 women/men aged 14-39). One third (27, 33%) was seizure free, 19 (24%) had generalized tonic-clonic seizures, and 53 (66%) myoclonic seizures during the last year. The most common AEDs measured included lamotrigine, valproate, and levetiracetam. Long-term TDM demonstrated variability over time expressed as intra-patient median values and inter-patient ranges of 19% (7-47) for valproate, 43% (10-83) for lamotrigine and 35% (6-111) for levetiracetam. Fifteen pecent (83/563) of serum concentrations were below the reference ranges and clould be due to variable adherence. Comedication with valproate for lamotrigine and pregnancy contributed to variability. The applicability is illustrated in a case of 10 years' follow-up in a young woman.\n\n\n\nThere was extensive pharmacokinetic variability of AEDs in and between patients with JME. A long-term TDM approach may contribute to closer monitoring of patients with JME and be used as a practical tool during clinical consultations.",
"affiliations": "Programme for Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; Department of Pharmacology, Section for Clinical Pharmacology, The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway. Electronic address: Cecilie.landmark@oslomet.no.;Programme for Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway.;The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway.;Department of Neurology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;Department of Neurology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.;Department of Neurology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; Department of Pharmacology, Section for Clinical Pharmacology, The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway.",
"authors": "Johannessen Landmark|Cecilie|C|;Fløgstad|Ida|I|;Baftiu|Arton|A|;Syvertsen|Marte|M|;Enger|Ulla|U|;Koht|Jeanette|J|;Johannessen|Svein I|SI|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D000077213:Lamotrigine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2019.05.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "155()",
"journal": "Epilepsy research",
"keywords": "Adherence; Antiepileptic drugs; Juvenile myoclonic epilepsy; Pharmacokinetic variability; Therapeutic drug monitoring",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D055118:Medication Adherence; D020190:Myoclonic Epilepsy, Juvenile; D009664:Norway; D012189:Retrospective Studies; D016896:Treatment Outcome; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106148",
"pmc": null,
"pmid": "31195184",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term follow-up with therapeutic drug monitoring of antiepileptic drugs in patients with juvenile myoclonic epilepsy.",
"title_normalized": "long term follow up with therapeutic drug monitoring of antiepileptic drugs in patients with juvenile myoclonic epilepsy"
} | [
{
"companynumb": "NO-ALKEM LABORATORIES LIMITED-NO-ALKEM-2019-07943",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"dr... |
{
"abstract": "In Burkina Faso, induced abortion is socially stigmatized, condemned, disapproved and legally restricted to cases of rape, incest, fetal malformation or endangerment to the life of the mother. Many women often resort to unsafe procedures to induce abortion, which puts their health at great risk. Misoprostol, which is officially restricted to the treatment of postpartum hemorrhage or post-abortion care, is also used illegally by women to terminate their pregnancies. Misoprostol represents an addition to the existing abortion methods, such as vacuum aspiration, which health workers have often used to induce abortion clandestinely. Many women also use misoprostol to self-induce abortions, replacing abortifacients such as herbal teas, potions, high doses of antimalarial drugs, or bleach. Despite the changes that occur in abortion access due to the use of misoprostol, little is known about what the drug means to its users and how this meaning can in turn influence the meaning of abortion. The aim of this paper is to describe how the use of misoprostol to terminate pregnancy contributes to changing women's perception of the meaning of abortion. This paper is based on ethnographic fieldwork conducted between March 2016 and February 2017 in the city of Ouagadougou, Burkina Faso. By examining the relation between the use of misoprostol and the meaning that women give to abortion, this study found that women experience abortion either spontaneously or using emergency contraception with misoprostol. Through the experience of women, this paper claims that the meaning of abortion should be seen as a social construct and fundamentally rooted in individual practices and experiences rather than being subject to dichotomist global discourse.",
"affiliations": "Institute of Health and Society, Faculty of Medicine, University of Oslo, 0315 Oslo, Norway.",
"authors": "Drabo|Seydou|S|0000-0002-3162-5316",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D016595:Misoprostol",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph16224425",
"fulltext": "\n==== Front\nInt J Environ Res Public HealthInt J Environ Res Public HealthijerphInternational Journal of Environmental Research and Public Health1661-78271660-4601MDPI 10.3390/ijerph16224425ijerph-16-04425ArticleA Pill in the Lifeworld of Women in Burkina Faso: Can Misoprostol Reframe the Meaning of Abortion https://orcid.org/0000-0002-3162-5316Drabo Seydou Institute of Health and Society, Faculty of Medicine, University of Oslo, 0315 Oslo, Norway; draboseyd@yahoo.fr12 11 2019 11 2019 16 22 442510 9 2019 08 11 2019 © 2019 by the author.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).In Burkina Faso, induced abortion is socially stigmatized, condemned, disapproved and legally restricted to cases of rape, incest, fetal malformation or endangerment to the life of the mother. Many women often resort to unsafe procedures to induce abortion, which puts their health at great risk. Misoprostol, which is officially restricted to the treatment of postpartum hemorrhage or post-abortion care, is also used illegally by women to terminate their pregnancies. Misoprostol represents an addition to the existing abortion methods, such as vacuum aspiration, which health workers have often used to induce abortion clandestinely. Many women also use misoprostol to self-induce abortions, replacing abortifacients such as herbal teas, potions, high doses of antimalarial drugs, or bleach. Despite the changes that occur in abortion access due to the use of misoprostol, little is known about what the drug means to its users and how this meaning can in turn influence the meaning of abortion. The aim of this paper is to describe how the use of misoprostol to terminate pregnancy contributes to changing women’s perception of the meaning of abortion. This paper is based on ethnographic fieldwork conducted between March 2016 and February 2017 in the city of Ouagadougou, Burkina Faso. By examining the relation between the use of misoprostol and the meaning that women give to abortion, this study found that women experience abortion either spontaneously or using emergency contraception with misoprostol. Through the experience of women, this paper claims that the meaning of abortion should be seen as a social construct and fundamentally rooted in individual practices and experiences rather than being subject to dichotomist global discourse.\n\nmisoprostolwomenabortionethnographyBurkina Faso\n==== Body\n1. Introduction \nAbortion is a complex subject that has given rise to intense debate over its “definition” and its social, political, and legal status. In general, the needs of women are not always taken into account during these debates [1]. Hence, the relevance of looking at the meaning that they give to an “interruption” of pregnancy, because their attitude towards abortion could depend on the meaning given to that interruption. The aim of this paper is to describe how the use of misoprostol to terminate pregnancy contributes to changing women’s perception of the meaning of abortion and it experience. \n\nMisoprostol is a drug that entered in the global market in the late 1980s, and it was originally produced for the prevention of gastrointestinal ulcers [2]. Misoprostol is also used in obstetrics and gynecology to induce labor, to prevent and treat postpartum hemorrhage, and to manage spontaneous abortion [3]. It is also gaining dominance worldwide as a drug that can be effective and safe to end a pregnancy when used at the right time and with the right dosage under the supervision of trained health professionals [4]. Given that sub-Saharan African countries have the highest rates of maternal mortality worldwide due to the consequences of abortion and hemorrhage [5], public health actors have advocated for increasing the availability and accessibility of misoprostol in order to reduce maternal deaths [6]. Abortion in the second trimester of a pregnancy can be performed by the administration of misoprostol using a variety of dosages and routes of supply [7,8]. This includes diagnosing and dating the pregnancy, administering the drug following instructionson appropriate use [9]. For example, although misoprostol is described as a safe method to terminating a pregnancy, it uses requires an appropriately trained provider in order to meet safety [10]. Therefore, accessing misoprostol does not necessarily guarantee safe abortion if the modalities of it uses are not respected. Improper use of misoprostol can lead to life-threatening complications such as collapse, bleeding and fever [11]. Moreover, a recent report on the issue of abortion worldwide suggests that clandestine abortion in legally restrictive settings is becoming relatively safer as misoprostol is replacing harmful methods [12]. Since 2005, the World Health Organization [8] has recognized misoprostol as a life-saving drug and recommended it on the list of essential medicines, although only “where permitted under national law and where culturally acceptable” in recognition of the controversial nature of misoprostol for use in induced abortion [8]. This stipulates that misoprostol be subject to specific use according to the social and political contexts of countries. \n\nIn Burkina Faso, induced abortion is socially stigmatized, condemned, disapproved [13] and legally restricted to cases of rape, incest, fetal malformation or endangerment to the life of the mother. Misoprostol is officially restricted to the treatment of postpartum hemorrhage and post-abortion care. Misoprostol also circulates informally in cities such as Ouagadougou and is often referred to locally as the ‘abortion drug’. Misoprostol represents an addition to the existing abortion methods, such as vacuum aspiration, which health workers have often used to induce abortions clandestinely. Many women also use misoprostol to self-induce abortions [13,14,15,16], replacing abortifacients such as herbal tea [17], potions, high doses of anti-malarial drugs, or bleach [4]. Misoprostol does indeed diversify abortion access sources, because its marketing in pharmacies and drug stores makes it possible to access the drug in secrecy [18]. Despite the changes that occur in abortion access due to the use of misoprostol, little is known about what the drug means to it users and how this meaning can in turn influence the meaning of abortion. \n\nThis study fits into the perspective of anthropological studies on the use of misoprostol to induce abortion by looking at how the drug can reframe the meaning of abortion for some of its users [18,19,20]. For example, De Zordo [19] shows how, in Brazil, induced abortion was tolerated morally among women who use misoprostol to induce abortion. Hardon and colleagues [20] discussed how girls use misoprostol in the Philippines for menstrual regulation (a euphemism for early abortion). Drawing on insights from this body of literature, this paper will discuss how using a pill rather than an invasive procedure could change the meaning of induced abortion from the perspective of women. \n\n2. Materials and Methods \nThis paper is based on ethnographic fieldwork conducted between March 2016 and February 2017 in Ouagadougou (Burkina Faso). I focused on women’s perspectives of and experiences in seeking out abortion, including medical abortion using misoprostol. I conducted participant observation in streets and their marketplace, interacting regularly with the various women and drug vendors. I observed pubs and the streets of Kwame Nkrumah, a main thoroughfare with many hotels, restaurants, pubs, frequented by men and women who work as waitresses or sex workers, often referred to collectively as “les filles de nuits” (girls of the night). This gave me opportunity to start conversation around the issue of abortion and to negotiate in-depth interviews with some of the women, who, because of their work, are at risk of unintended pregnancy, abortion and their consequences [21].\n\nIn order to understand the context of drug sales and the interactions between drug sellers and consumers, I conducted participant observations and informal discussions with street drug vendors by spending time with them in their marketplace. During events such as The Panafrican Film and Television Festival of Ouagadougou, the public authorities officially establish a merchant street where traders come to expose their products. Drug vendors participate in these activities by exposing and selling their product for one week. I stayed in the store of one of the drug vendors who was selling non-Western contraceptive methods and other drugs purchased by women. The long hours spent waiting there (3 to 6 h) gave me both an opportunity to talk with both the drug vendor and some of his clients. \n\nIn addition to participant observation, I conducted in-depth interviews with 46 women (in the perspective of the broad PhD research) about their reproductive trajectories, their perceptions and practices of contraceptive methods and abortion drugs and the decision-making processes and networks involved in the procurement of misoprostol. Health care workers assisted me in identifying women who had sought family planning and post-abortion care and who were willing to participate. I used my social network to identify other participants from the general population. This consisted of asking women who were more or less close to me (neighborhood, former classmates, friends, etc.) and who agreed to participate in this study. Subsequently, I relied on these women to access other women (friends of my friends, etc.) who were also willing to participate in this study. Of the 46 women I interviewed, 16 reported that they had undergone induced abortions in the past. These 16 interviews form the basis of the analysis in this paper. Apart from two women, I met in post-abortion care services, the rest of the women (14) I met outside of a health center. Among this group, nine were single women, four were co-habiting with a man, two were married and one was widowed. Seven of these women were working as servers in a pub, three were students, three were petty traders, one was a maid, one a housewife and one a public servant. Five of the women in this group had had more than one abortion. Together, these 16 women had 23 abortions between 2010 and 2017. Ten of them reported using misoprostol to terminate one or more pregnancies (five women used it vaginally with the support of the abortion provider and six women used it orally themselves or after receiving instruction from abortion providers or friends), while other methods included manual vacuum aspiration potassium permanganate, Chinese pills and recipes made from plants. The ten women who reported using misoprostol for abortion did so on pregnancies ranging from 1½ to 4 months. Among these women, one used the drug without confirming the pregnancy while the other one did not know how far along she was in her pregnancy at the time of using misoprostol. Seven out of the 16 women’s interviews are used in this paper because their cases are more illustrative of women’s abortion experiences and related issues.\n\n2.1. Data Analysis and Ethical Issues\nI conducted interviews in French, Mooré or Dioula depending on participants’ preferences. I also fluently speak the three languages. I tape-recorded the interviews (except 3 of them who were more comfortable with note taking) and they were transcribed verbatim. Interviews lasted between 20 min and one hour and 30 min. A research assistant transcribed the interviews and those recorded in Mooré or Dioula were translated into French. I did the final editing, checking all the transcripts in order to ensure accurate transcription and translation. \n\nThe data analysis process was guided by a thematic approach that was both deductive and inductive [22]. The data was reviewed with certain preconceived categories derived from previous studies and from my own research experience [1,13,23]. For examples, theme such as women’s reproductive experience, affective trajectories, relationships with contraception and abortion technologies and the decision-making processes in relation to these methods are illustrative of the deductive analysis. The inductive analysis concerns themes that emerge directly from the data using inductive coding. In this framework, the transcripts were carefully read in order to identify the emerging themes. Phrases and sentences related to abortion experience and the way they define or perceived it were coded in the margins of the transcript sheets.\n\nThe themes identified in the research drew out historical details of the women’s lives, while pointing out the facts, practices or events that dealt with their reproductive life. The events were related to each other by taking into account their chronology. The approach makes it possible to see, for example, when and how the prevention, the occurrence and the termination of a pregnancy occurred in the person’s life; the motivations and facts that contributed to the occurrence of these events, their perception and so on. This data summarized the stories of women. \n\nCross checking research material (interviews, field notes, and observation) and the summary of women’s stories allowed me to write a “problematized” portrait, i.e., a portrait of a research participant around an issue they experienced and described based on a specific context [24].\n\nI used some of the portraits and excerpts from interviews with women that have used misoprostol to terminate a pregnancy to illustrate my findings. The quotes that I have chosen to use to illustrate the findings have been translated from French to English. I obtained ethical approval for this study from the Ethical Committee of Burkina Faso and the Norwegian Centre for Research Data. I read out loudly informed consent forms to the research participants, who provided oral consent by their own wish. Oral consent was also the most suitable because of the sensitivity of the topic for both health care providers, drug vendors and women. Despite reading informed consent, I tried to remind my participants of my good intentions. For example, I made women understand “My goal is not to judge but to understand...”. This attitude allowed me to establish a climate of trust with participants so that they would feel comfortable talking about their reproductive life experiences. I told all participants they could withdraw from this study at any time or choose not to participate in this study. The names of participants cited in the quotes are pseudonyms.\n\n2.2. Abortion Debate and the Role of Technology \nAbortion remains a moral issue that raises debate that is usually framed as a battle between the fetus’s right to life and the woman’s right to choose [25]. At this level, different conflicting points of view are clear: one position maintains that the fetus is a life and claims that abortion should be criminalized [26]. Another position counters this argument by asserting that the fetus is not a life and that policy must be directed toward protecting a woman’s ability to control her own body by letting her choose whether to have an abortion or to carry a pregnancy to term [26]. The players in this debate involve a list of non-exhaustive actors, including religious actors, less well-known opponents of abortion, feminist groups, medical circles, family planning agencies, etc. [25,27]. Beyond discussion about the status of the fetus and the rights of women, debate also concerns a struggle over what the goal for abortion policy should be [27]. At this level, the debate focuses on different issues ranging from the recognition of abortion as a public health problem to the recognition of abortion as a woman’s right [1]. \n\nThe issue of abortion as a public health problem has been addressed at various conferences and has been focused on the health consequences of unsafe abortions considered as major public health problems. Unsafe abortion, described as a cause of maternal morbidity and mortality in countries where abortion is illegal [28], has introduced discussions on the decriminalization of abortions. However, opponents of the decriminalization of abortion hardly recognize the link between illegality and the associated risks. For the latter, decriminalization would increase the occurrence of unsafe abortions, despite recent scientific evidence that has shown that the prevalence is low and relatively stable in countries where abortion is legal [29] in contrast to countries where abortion is illegal [1]. Moreover, given the lack of global consensus, emphasis has been placed on the prevention of abortions through universal access to family planning services, post-abortion care and the need for governments to guarantee individuals the exercise of sexual and reproductive rights. \n\nRegarding abortion as women’s rights, none of the international conferences have admitted a right to abortion and referred the decision back to the national authorities of countries [30]. As a result, in many countries, the legal status of abortion is more about health concerns than rights, as claimed by feminist movements since the 1960s. \n\nFurthermore, technology has not remained on the sidelines of the abortion debate. Callahan [31] described in five points how scientific development could reframe abortion debate through several implications [31]. First, the scientific developments have legal implications, as they can be significant in undercutting important factual assumptions underlying earlier court decisions. Second, the developments may have psychological implications, because new evidence may motivate people to think in different ways about their beliefs. Third, the scientific developments can have social implications in placing abortion in a different social context. Fourth, the developments may have political implications by serving as effective political capital if cleverly deployed. Fifth, the developments can have moral implications by prodding people to examine their consciences or by provoking new moral arguments. \n\nIn practical terms, technological changes, such as fetal photography, ultrasound, advances in care for preterm infants, and fetal surgery, have facilitated personification of the fetus and challenged previous constructions of boundaries between fetus and infant [31,32]. The antagonist groups have used these different technologies in order to strengthen their positions. For example, the actors who think that women have the basic human right to decide when and whether to have children have debated the relevance of appropriate gestational age limits [32], while actors advocating against abortion have helped to shape this debate by using fetal images and by interpreting them in ways that suggest abortion is equivalent to murder [33]. As we can see, technology is making the abortion debate more complex, because different groups of people exploit it to support their perspectives, which contributes to perpetuation of the antagonistic positions. However, the complexity of the abortion debate involves historical and cultural meanings specific to each country [27]. \n\n2.3. Understanding the Social Context and the Illegal Circulation of Misoprostol \nThe Burkinabe context offers a complex landscape for studying the use of misoprostol to terminate pregnancy. Burkina Faso is a sub-Saharan African country located in West Africa. The average age at first marriage is 17.9 years old, with nearly one-third of girls married between 15 and 19 years old and two-thirds married by the time they turn 24 years old [34]. The fertility rate was estimated at 5.71 children per woman by the World Bank in 2017. In Burkina Faso, sexuality in marriage is expected as elsewhere. However, sex also occurs frequently outside of marriage [35]. This increases the risk of unintended pregnancies. According to Bankole and colleagues [4], one-third of all pregnancies each year in Burkina Faso are unintended, and one-third of unintended pregnancies are ended by abortion. In rural areas, the abortion rate is slightly lower (22 per 1000 women) as compared to that in urban areas (42 per 1000). \n\nThe practice of abortions, like in many societies [36], is subject to social disapproval in Burkina Faso. Abortion experiences are intimate and confined to silence [35]. Many women often resort to unsafe procedures to induce abortion, which can create great risks to their health. In general, half of women who induce their own abortions are estimated to experience complications as compared with approximately two in 10 women who go to health care providers [4] offering illegal abortions. The government’s principal policy response to the issue of unsafe abortions has been the implementation of a post-abortion care policy to treat the complications of unsafe abortions [30,37] through manual vacuum aspiration and misoprostol. \n\nMy fieldwork focused on Ouagadougou, a city of 2.7 million inhabitants [38], which is also Burkina Faso’s administrative and economic center. In Ouagadougou, there is no access to abortion care in the public sector, except in the circumstances stipulated by law. Comprehensive post-abortion care services are offered in secondary and tertiary health care facilities and in some primary health care facilities in the public sector as well as in certain private sector and Non-Governmental Organizations facilities [39]. Misoprostol can be purchased for reproductive health indications by prescription in hundreds of pharmacies in the city [40]. There are mechanisms in place in health facilities to prevent misoprostol from being used outside the framework of the management of incomplete abortions and in the treatment of postpartum hemorrhage (Ouattara et al. 2019 forthcoming). However, the permissiveness of the drug distribution system in Burkina Faso that allows individuals to access the drug without showing a prescription generates conditions that favor illegal abortion [16]. In this context, the circulation of misoprostol obeys the same logic of drug exchange in developing countries where Van der Geest and Whytes [41] have shown that it often circulates as a commodity that can be sold and purchased [41]. Drug vendors in pharmacies, health workers and sex workers are among the actors involved in the network that enables women to access misoprostol illegally (Drabo 2019 forthcoming). \n\n2.4. Misoprostol Is Changing Access to Abortion \nThe abortion experiences of women show that misoprostol has changed access to induced abortions, because it allows them to have abortions discreetly and at a relatively cheap cost as compared to other abortion methods, such as manual vacuum aspiration. Women described how misoprostol could be used at home, in a pub, guesthouse or any place to induce abortion. Here, 23-year-old Awa (single) explains her experience when she resorted to misoprostol to terminate a three-month pregnancy: \n\n“My boyfriend contacted a doctor who gave us an appointment in front of a guest house. My boyfriend paid for the room and then waited outside. I went inside with the doctor who put a white pill inside me. After that, I did not see him again. When I arrived home, I started bleeding a bit and it came out.” \n\nThese examples show how misoprostol enables clandestine abortion services to work discretely, by removing the procedure from the health care setting where providers may risk prosecution if complications occur. In addition to meeting the need for discretion, misoprostol also changes the cost of abortion services. \n\nWomen report that abortion with misoprostol was relatively affordable, around 15 USD, as compared to illegally induced abortions using manual vacuum aspiration, which can cost 45 USD. However, the price of misoprostol varies depending on how the product is accessed. It is relatively cheap when women procure it to have a self-induced abortion as compared to when they use a health worker. However, some women I spoke with had an abortion without paying money, because their acquaintances gave them misoprostol free. For example, Diane a 35-year-old woman lived with her partner for 17 years with whom she had two children. Her partner did not want another child. After she announced her third pregnancy, he asked her to have an abortion and threatened to leave her if she kept the pregnancy. Diane decided to contact one of her friends, a medical doctor, to obtain misoprostol, and he gave it to her free of charge. As she explained: \n\n“When I had my problem, I got the product for free. A friend helped me to get it from another friend. He did not buy it either, because they are both health professionals and they mutually support each other. The other friend could not refuse, because he knows that one day he may also need help (not only abortion) from my friend.” \n\nFurthermore, some of the research participants described how they obtained misoprostol from female friends or relatives who had used it to self-induce abortion. These female friends or relatives gave the remaining pills from the packet they purchased as a gift. Although she has never had an abortion, one woman in my study confided that she has misoprostol because her cousin gave her some tablets in case she would need them one day. She interrupted the discussion to locate the tablets and showed me a blister pack with six tablets missing. This fact of giving misoprostol means that the abortion of one woman can allow the abortion of another woman. \n\nIn sum, misoprostol through the changes that it brings in terms of access to abortion is a response to the demands or the expectations of women seeking to terminate a pregnancy within the context of the restrictive abortion law in Burkina Faso. \n\n2.5. When Misoprostol Turns Induced Abortion to “Spontaneous Abortion”\nMisoprostol plays an important role in the abortion experiences of women given that it has diversified pregnancy termination methods in addition to existing methods, such as manual vacuum aspiration and curettage. By describing their use of misoprostol and the abortion process, some of the participants, such as Adjara, stated that the drug interrupts pregnancy like a spontaneous abortion. \n\nAdjara is a 37-year-old woman who started using contraceptives at the age of 18 with the intention of avoiding pregnancy before marriage. During my interviews with her, she reported that a pregnancy before marriage would be unwelcome in her family because of their traditions and religious affiliation. As she said, “I come from a Muslim family and besides we have our tradition when you take a pregnancy automatically it is outside.” Later on, for fear of illness and being overweight, she decided to stop taking contraception after 4 years of use. Immediately after this cessation, she experienced three pregnancies before her marriage and decided to get rid of them. The first pregnancy was interrupted by a curettage performed by a health worker. She terminated the last two pregnancies herself using misoprostol, which she discovered through one of her acquaintances. Adjara declared that she used misoprostol the first time on a one-and-a-half-month pregnancy and for the second time, she did not confirm the pregnancy before using the drug. Comparing the two methods of abortion (curettage and misoprostol), Adjara said: \n\n“Since I discovered misoprostol I did not do curettage again. The curettage is very painful, and you do not know who is fiddling you. I do not know how to express it, but it is very painfully. While with misoprostol, you swallow and the next day you have small stomachache; then, you go to the toilet, you feel it goes down slowly, and then you take antibiotics after. It is a bit like having a spontaneous abortion...”. \n\nThe example of Adjara shows that past abortion experiences can play an important role in the way women build their perceptions about abortion, because the fact of having experienced several abortions makes it possible to make comparisons between different episodes and methods. We see how Adjara refers to her three abortion experiences to state her preference for misoprostol over curettage. She justified her preference for misoprostol based on its process, which is less painful and interrupts pregnancy like a spontaneous abortion. Furthermore, Adjara’s reference to spontaneous abortion, even though she has not reported having had one, can express her attempt to describe a pregnancy termination with a positive note given that spontaneous abortions in Burkina Faso are morally accepted as compared to induced abortions. \n\n2.6. Misoprostol Is Like Emergency Contraception Pill \nThe use of emergency contraceptives is part of the reproductive experience of women. In general, women use emergency contraceptives when they are in a situation that they consider to be at risk for pregnancy. Through their discourse during interviews and informal discussions, the use of emergency contraception, which they commonly call “norlevo”, is a common practice to avoid pregnancy, as testified by the following example of Veronique. Veronique is a 35-year-old woman living in a union with a man, and she was a mother of two children at the time of the interviews. She identified herself as a religious person, meaning she is practicing a religion (Protestant). Veronique used a contraceptive method; the first time was in 2012 after her second delivery by resorting to pills and injections. Afterwards, she stopped taking them, because she was not living in the same city with her partner. She said, “To take contraceptive methods is to say that we are sexually active. I don’t live with my husband, and I am not sexually active. So, I decided not to take contraception anymore.” However, Veronique confided in me that she has resorted to emergency contraception in case of sexual intercourse during a period in which she is likely to become pregnant. She said, “For us who are religious, it is acceptable, because nothing proves that there was going to be a pregnancy.” \n\nFurthermore, although most women I interviewed admitted to have used the morning-after pill at least once in their life, some of them found it ineffective in avoiding a pregnancy as explained by Nina, a 39-year-old woman who ironically declared: “Yes, I know I’ve used this before, but it does not work all the time. If you want take a pill of few seconds, it does not work.” Through this quote, Nina stresses that if there was a pill of some second unlike that of 72 h (morning-after pill), it will not work for everyone. Due to the uncertainties associated with the efficacy of the morning-after pill, some of the women I interviewed prefer to resort to misoprostol once they have a delay in the onset of menstruation: “Yes, because as soon as you know you have a delay, you take it.” These words of Adjara were confirmed during informal discussions I had with women in a maquis in the city of Ouagadougou. In this environment, the use of misoprostol is often trivialized, because the girls refer to the drug to tease each other. As explained by Flora (33 years old, living with a man) during informal discussion: “When you see a friend who is sad or who is looking sad, you propose to her to slip two tablets of miso in her beer in case there is a delay in her period that is worrying her” (laugh). \n\nAs can be seen, the experiences and discourse of women shows that they tend to substitute misoprostol for an emergency contraception pill, especially since some of them do not hesitate to describe misoprostol by equating its mode of action with that of “norlevo” (emergency contraception). As does Flora, a single woman who during the interview has declared to having already resorted to misoprostol to stop a pregnancy (the pregnancy was two months): “If you know the effect of norlevo then you know the effect of misoprostol (Cytotec). When you take it after your dangerous period, it is only blood that you will see coming out later. …” (Flora, 33 years old, living with a man). \n\nComparing misoprostol with emergency contraception pills makes one think about the following syllogism: if using emergency contraception does not mean having an abortion and misoprostol acts like emergency contraception, then the use of misoprostol does not necessarily mean you are having an abortion. Furthermore, it should be noted that women who tend to have a positive discourse on the use of misoprostol as a method of terminating a pregnancy have used it either on a confirmed pregnancy at an early stage (1 to 2 months) or after a delay in their menstrual cycle (2 weeks to 1 month). \n\nExamining the relation between the use of misoprostol and the meaning that women give to abortion, we see that women view an abortion either as spontaneous or as emergency contraception. This reference to spontaneous abortion and emergency contraception appears to be a way for women to confess their abortion with understatement in order to present a picture of abortion that is socially and legally acceptable. Indeed, in Burkina Faso, spontaneous abortion is considered a misfortune that can generate compassion for the “victim,” while emergency contraception reminds one of contraception, meaning a prevention of pregnancy before conception, which is also an issue that the women accept compared to abortion (which is a termination of the pregnancy after conception). The fact that they answer the question as to whether they have already voluntarily terminated a pregnancy by naming their experience shows that women do not deny that what they performed was an abortion, but they simply decide to present it in other way thanks to misoprostol and its mode of action. \n\n2.7. Women’s Abortion Experiences with Misoprostol \nThe use of misoprostol for abortion is not equally available to all women. Indeed, women’s stories show that access to abortion is not a foregone conclusion. A forthcoming paper on the domestication of misoprostol by women highlights that terminating a pregnancy with misoprostol outside legal frameworks does not always turn out as expected. In this regard, some women can obtain medical abortion with misoprostol by resorting to private clinics. Women who do not have money to buy misoprostol are more likely to be victims of sexual harassment or sexual abuse from men that offer abortion services. Some women will perform self-abortion by administering drugs, but in most instances, they resort to misoprostol in contexts characterized by uncertainties related to a lack of information about the pregnancy and the drug. As illustrated by the case of Charlotte:\n\nCharlotte, 26, is a student and mother of a 7-month-old child. After the birth of her child, charlotte chose not to use any contraceptive method because she feared the side effects. Resuming sexual intercourse, Charlotte said she was afraid of becoming pregnant because her partner refused to use condoms. After a two-month delay in her menstrual cycle, Charlotte thought she was pregnant despite the negative results of a pregnancy test she did herself. To remove doubt, she decided to terminate the “suspected” pregnancy. Charlotte decided to go to a pharmacy in the city center of Ouagadougou to obtain an abortion pill, she explained: \n\n“Once in the pharmacy. I told him that I have a young child and I realized that I am pregnant. It will be difficult for me to keep this pregnancy and to manage the other child. After my explanations, he told me there is a product that can terminate the pregnancy but without a prescription, he cannot sell it. However, he later reassures me that he can help me if I have money to buy the drug. The drug cost 11,000 of the West African CFA franc (XOF) (1 US equals approximatively 590 XOF). I did not have enough money that day and I had to return to the pharmacy 3 days later after getting money from a friend. The drug vendor gave me a tablet of misoprostol and told me that I should swallow four pills three times every four hours. However, before I left the pharmacy, he told me he is not responsible for any problem that will happen…”.\n\nCharlotte’s experience shows her willingness to use misoprostol without being sure of being pregnant. In addition, she has access to the drug from the seller, who shows her a regimen without knowing her gestational age and his disengagement from the rest of the abortion process. It is clear that in these circumstances, the risk of the improper use of the drug becomes clear. Later in the discussion, Charlotte confessed that she resigned herself to not using the drug until the pregnancy becomes evident. Another woman, Samira, a 21-year-old woman (single) working in a pub, obtained misoprostol from a friend with minimal knowledge on the misuse of the product. During the interviews conducted with her, she confided that she was three months pregnant and decided to terminate it. She obtained misoprostol from a friend who did not tell her how to use it. She took the entire tray of pills at the same time (14 tablets). A few minutes later, she was admitted to hospital due to dizziness and pelvic pain. \n\nFor other women, accessing abortion means experiencing failed abortion as illustrated by the case of Anna, a 30-year-old who became pregnant with her foreign boyfriend. She was not sure about how far along in the pregnancy she was but thought that it had been more or less three months since the baby was conceived. She worked as a hairdresser and earned between 15000 XOF to 20000 XOF a week. She supplemented her meagre income through sex work. She decided to terminate the pregnancy since she was concerned that her boyfriend would take the child to his home country. As she said: “I am not going to struggle to give birth to a child and they will come and take it from me one day”. When Anna was one month pregnant, she asked a friend to escort her to a woman who she knew that conducted abortions in her home. According to Anna, this abortion provider was not a health care worker, but learned how to conduct abortions after working with a health care worker. \n\nAnna and her friend visited the woman several times over a period of eight days before she finally agreed to help them. She asked them to pay 20,000 XOF, before placing a white product (I assumed it could be misoprostol) in Anna’s vagina and explaining that once Anna reached home, the fetus would be expelled. Unfortunately, the pregnancy was still intact after a week. After this failed abortion attempt, Anna was afraid to go back to see the woman because their previous meetings were difficult. With the help of the same friend, she decided to go to a clinic known to practice clandestine abortions three weeks later after the first attempt. Once she reached the clinic, the man who owned the clinic requested that she pay 2000 XOF for the examination. After the examination, he fixed the price of Anna’s abortion at 50,000 XOF and gave her an appointment for the same afternoon. Anna did not have enough money but decided to go to the appointment anyways with the intention of negotiating a discount. Once in the clinic, a secretary in the clinic discreetly informed Anna that she knew a place where Anna could have an abortion for less. Anna accepted the offer and was directed to the home of another woman. Anna did not know anything about the professional background of the woman, beyond that she offered abortion services. The woman performed Anna’s abortion in her house (abortion provider) by aspiration at a cost of 30,000 XOF.\n\nAnna’s experience illustrates that accessing misoprostol outside legal frameworks may not guarantee access nor a successful abortion. Given the illegality of the abortion, in the case of failure, women are not able to hold the abortion providers accountable. Rather, they go to official health facilities to receive support for treatment if complications occur, or resort to another abortion provider until they are “satisfied”, such as in Anna’s case. In such circumstances, women may face unplanned expenses or experience delays in receiving the right care after starting the abortion process. \n\n3. Discussion\nThe aim of this paper was to describe how the use of misoprostol to terminate pregnancy contributes to changing women’s perception of the meaning of abortion. Based on ethnographic research, I have highlighted how the use of misoprostol allows women to access abortion at a relatively cheap cost, which corroborates with findings from other studies [7,42].\n\nFor women who have access to misoprostol, its use to stop a pregnancy influences how they define abortion, especially in view of the fact that misoprostol, as a technical object, can be a meaning-making vehicle [43]. That is to say, that it can impose a certain frame of thought [44]. By examining the relation between the use of misoprostol and the meaning that women give to abortion, this study has shown that, with misoprostol, women experience abortion either as spontaneous or as using emergency contraception. Thus, with misoprostol, the experience of abortion becomes different due to some of the following reasons: the early abortions women have allows them to see blood instead of a “constituted” fetus after expulsion; the process of pregnancy interruption is less painful, leading to a post-abortion period with less trauma; in addition, the fact of anticipating the use of misoprostol without confirming a pregnancy when they have a delay in their menstrual period allows them to maintain doubts about abortion and to equate the use of the drug to a contraceptive method. Furthermore, this reference to spontaneous abortion and emergency contraception allows them to present a picture of abortion that is socially, legally and morally acceptable. These findings confirm other anthropological studies [18,19] that have highlighted how misoprostol changes the meaning of abortion by making it a morally acceptable practice. The attitude of women reminds us that the meaning of abortion depends on the beliefs, perceptions and experiences of individuals. Thus, women’s “encounter” with misoprostol and its mechanisms of action help to “shape” their perception of abortion.\n\nFurthermore, one of the major changes that misoprostol has brought to the abortion experience of women is the relative autonomy it guarantees from physicians and their instruments [45]. As with other abortion drugs, such as RU-486 (mifeprostol), misoprostol is a technology that allows women to be actors during the abortion procedure, which is in contrast with surgical methods that reduces them to the status of patients and dependent on medical actors to terminate their pregnancy [46]. This situation reduces the social and medical constraints that limit access to abortions (ibid). However, the context in Burkina Faso allows for some nuances, because women do not have equal access to abortion drugs, such as misoprostol. For example, a recent study in Ouagadougou has shown that the use of misoprostol is predominantly among women who have secondary and post-secondary education and who have high socioeconomic status [14]. Indeed, the introduction and use of misoprostol in Burkina Faso in the context of the restrictive abortion law gives opportunities to individuals with strong social networks and negotiating power to access misoprostol relatively easily, while those less powerful still struggle (Drabo 2019 forthcoming). Access to misoprostol through friends and drug vendors in pharmacies for abortion does not necessarily equate with quality, because the experience of women in this study and other studies has shown that the information provided by individuals working in pharmacies and drug shops is often poor, with few advising an effective regimen or not giving information on potential complications if they occur [47].\n\nFor poor women, the purchase and the use of misoprostol outside legal frameworks means risking sexual violence, misusing the product due to a lack of proper information with the risk of health complications, and experiencing inefficiency of the product when purchased from illegal abortionists, and the additional costs that this entails in the abortion-seeking process. These issues are in line with the findings of Zordo [19], who has shown in her studies in Brazil that the lack of legal access to misoprostol and to information on its safe use makes its purchase sometimes difficult and its use dangerous for low-income women. Despite accessing misoprostol, these women’s abortion experiences fall into the category of “less safe” abortion because of the lack of adequate information and support from trained individuals [10]. In addition, when abortion providers use their power to exploit women’s vulnerability by abusing them sexually, it is clear that for these women, the route to accessing a safer abortion, medically speaking, can be unsafe (Drabo 2019 forthcoming). The legal context of accessing misoprostol contributes to perpetuating forms of violence that undermine women’s sexual and reproductive health rights.\n\nUnderstanding abortion experience, the risks associated with the use of misoprostol and inequalities in drug access could elicit policy changes by raising awareness of constraints related to the informal access of misoprostol and its health consequences. That is what makes this ethnography valuable.\n\nThis study has some limitations. The findings presented are from interviews with a relatively small group of participants recruited in the capital city and, thus, the views are not necessarily generalizable to all women. In particular, the majority of the women interviewed for this paper were recruited outside of health care facilities with the exception of two. The sample therefore is unlikely to represent the full spectrum of women’s abortion experience, particularly those who are admitted to hospital for post-abortion complications. \n\n4. Conclusions\nThrough the experiences of women cited in this paper, the meaning of abortion should be seen as a social construct and fundamentally rooted in individual practices and experiences. Rather than being subject to dichotomist discourses within the arena of global health. Furthermore, changes brought by misoprostol in term of access to abortion and the relative cheapness of abortion that results from the use of the drug make it likely that women will continue to resort to it. Providing women with knowledge about proper usage of the drug will be a relevant public health intervention that could reduce the health risks associate with the improper use of misoprostol. The Uruguay model could inspire this intervention by involving pharmacists/drug vendors and health workers in the process of evidence-based information on the safe use of misoprostol [48].\n\nFunding\nThis research was funded by the Norwegian government PhD Quota Scholarship, through the Norwegian State Education Fund, Lånekassen.\n\nConflicts of Interest\nThe author declares no conflict of interest.\n==== Refs\nReferences\n1. Guillaume A. Rossier C. Reeve P. Abortion around the world. An overview of legislation, measures, trends, and consequences Population 2018 73 217 306 \n2. Wilson K.S. Garcia S.G. Lara D. Misoprostol Use and Its Impact on Measuring Abortion Incidence and Morbidity Methodologies for Estimating Abortion Incidence and Abortion-Related Morbidity: A Review Guttmacher Institute New York, NY, USA 2010 191 201 \n3. Tang J. Kapp N. Dragoman M. De Souza J.P. WHO recommendations for misoprostol use for obstetric and gynecologic indications Int. J. Gynecol. Obstet. 2013 121 186 189 10.1016/j.ijgo.2012.12.009 23433680 \n4. Bankole A. Hussain R. Sedgh G. Rossier C. Kaboré I. Guiella G. Unintended Pregnancy and Induced Abortion in Burkina Faso: Causes and Consequences Guttmacher Institute New York, NY, USA 2014 \n5. Say L. Chou D. Gemmill A. Tunçalp Ö. Moller A.-B. Daniels J. Gülmezoglu A.M. Temmerman M. Alkema L. Global causes of maternal death: A WHO systematic analysis Lancet Glob. Health 2014 2 e323 e333 10.1016/S2214-109X(14)70227-X 25103301 \n6. Fernandez M.M. Coeytaux F. De León R.G.P. Harrison D.L. Assessing the global availability of misoprostol Int. J. Gynecol. Obstet. 2009 105 180 186 10.1016/j.ijgo.2008.12.016 19286183 \n7. Ngai S.W. Tang O.S. Ho P.C. Prostaglandins for induction of second-trimester termination and intrauterine death Best Pract. Res. Clin. Obstet. Gynaecol. 2003 17 765 775 10.1016/S1521-6934(03)00068-3 12972013 \n8. World Health Organization Priority Life-Saving Medicines for Women and Children 2012 World Health Organization Geneva, Switzerland 2012 \n9. World Health Organization Safe Abortion: Technical and Policy Guidance for Health Systems World Health Organization Geneva, Switzerland 2012 \n10. Ganatra B. Gerdts C. Rossier C. Johnson B.R. Tunçalp Ö. Assifi A. Sedgh G. Singh S. Bankole A. Popinchalk A. Global, regional, and subregional classification of abortions by safety, 2010–2014: Estimates from a Bayesian hierarchical model Lancet 2017 390 2372 2381 10.1016/S0140-6736(17)31794-4 28964589 \n11. Pawde A.A. Ambadkar A. Chauhan A.R. A study of incomplete abortion following medical method of abortion (MMA) J. Obstet. Gynecol. India 2016 66 239 243 10.1007/s13224-015-0673-1 27382216 \n12. Singh S. Remez L. Sedgh G. Kwok L. Onda T. Abortion Worldwide 2017: Uneven Progress and Unequal Access Guttmacher Institute New York, NY, USA 2018 \n13. Drabo S. Access to Post Abortion Care (PAC) in Burkina Faso: An Ethnographic Study Master’s Thesis University of Oslo Oslo, Norway 2013 \n14. Baxerres C. Boko I. Konkobo A. Ouattara F. Guillaume A. Abortion in two francophone African countries: A study of whether women have begun to use misoprostol in Benin and Burkina Faso Contraception 2018 97 130 136 10.1016/j.contraception.2017.10.011 29104024 \n15. Ouédraogo R. Sundby J. Social Determinants and Access to Induced Abortion in Burkina Faso: From Two Case Studies Obstet. Gynecol. Int. 2014 2014 402456 10.1155/2014/402456 24790605 \n16. Ouedraogo R. «L’avortement, Ses Pratiques et Ses Soins». Une Anthropologie des Jeunes au Prisme des Normes Sociales et des Politiques Publiques de Santé au Burkina Faso PhD Thesis Université de Bordeaux Bordeaux, France \n17. Dehane K.L. Abortion in the north of Burkina Faso Afr. J. Reprod. Health 1999 3 40 50 10.2307/3583360 \n18. Moland K.M. Haukanes H. Tadele G. Blystad A. The paradox of access-abortion law, policy and misoprostol Tidsskrift for den Norske Laegeforening: Tidsskrift for Praktisk Medicin ny Raekke 2018 137 10.4045/tidsskr.17.0809 29357663 \n19. De Zordo S. The biomedicalisation of illegal abortion: The double life of misoprostol in Brazil História Ciências Saúde-Manguinhos 2016 23 19 36 10.1590/S0104-59702016000100003 27008072 \n20. Hardon A. Idrus N.I. Hymans T.D. Chemical sexualities: The use of pharmaceutical and cosmetic products by youth in South Sulawesi, Indonesia Reprod. Health Matters 2013 21 214 224 10.1016/S0968-8080(13)41709-3 23684204 \n21. Weldegebreal R. Melaku Y.A. Alemayehu M. Gebrehiwot T.G. Unintended pregnancy among female sex workers in Mekelle city, northern Ethiopia: A cross-sectional study BMC Public Health 2015 15 40 10.1186/s12889-015-1366-5 25636515 \n22. Braun V. Clarke V. Using thematic analysis in psychology Qual. Res. Psychol. 2006 3 77 101 10.1191/1478088706qp063oa \n23. De Oliveira Martins L.P. Technoecologies of Birth Control: Biopolitics by Design Ph.D. Thesis Universität der Künste Berlin Berlin, Germany 2017 \n24. Adjamagbo A. Koné P.A. Situations relationnelles et gestion des grossesses non prévues à Dakar Population 2013 68 67 96 10.3917/popu.1301.0067 \n25. Jotkowitz A. Zivotofsky A.Z. The ethics of abortions for fetuses with congenital abnormalities Eur. J. Obstet. Gynecol. Reprod. Biol. 2010 152 148 151 10.1016/j.ejogrb.2010.05.030 20561739 \n26. Smith A. Beyond Pro-Choice Versus Pro-Life: Women of Color and Reproductive Justice NWSA J. 2005 17 119 140 10.2979/NWS.2005.17.1.119 \n27. Kulczycki A. The Abortion Debate in the World Arena Routledge New York, NY, USA 1999 \n28. Shah I.H. Åhman E. Unsafe abortion differentials in 2008 by age and developing country region: High burden among young women Reprod. Health Matters 2012 20 169 173 10.1016/S0968-8080(12)39598-0 22789095 \n29. Sedgh G. Bearak J. Singh S. Bankole A. Popinchalk A. Ganatra B. Rossier C. Gerdts C. Tunçalp Ö. Johnson B.R. Abortion incidence between 1990 and 2014: Global, regional, and subregional levels and trends Lancet 2016 388 258 267 10.1016/S0140-6736(16)30380-4 27179755 \n30. Ouattara F. Storeng K.T. L’avortement volontaire au Burkina Faso: Quand les réponses techniques permettent d’éviter de traiter un problème social Autrepart 2014 70 109 123 10.3917/autr.070.0109 \n31. Callahan D. How Technology Is Reframing the Abortion Debate Häst. Cent. Rep. 1986 16 33 42 10.2307/3562468 \n32. Norris A. Bessett D. Steinberg J.R. Kavanaugh M.L. De Zordo S. Becker D. Abortion Stigma: A Reconceptualization of Constituents, Causes, and Consequences Women Health Issues 2011 21 S49 S54 10.1016/j.whi.2011.02.010 21530840 \n33. Michaels M. Morgan L.M. Introduction: The fetal imperative Fetal Subjects, Feminist Positions University of Pennsylvania Press Philadelphia, PA, USA 1999 1 9 \n34. INSD et ICF International Enquête Démographique et de Santé et à Indicateurs Multiples du Burkina Faso 2010 INSD et ICF International Calverton, MD, USA 2012 \n35. Rossier C. Guiella G. Ouedraogo A. Thiéba B. Estimating clandestine abortion with the confidants method—Results from Ouagadougou, Burkina Faso Soc. Sci. Med. 2006 62 254 266 10.1016/j.socscimed.2005.05.024 16076516 \n36. Boltanski L. La Condition Foetale: Une Sociologie de L’engendrement et de L’avortement Gallimard Paris, France 2004 \n37. Storeng K.T. Ouattara F. The politics of unsafe abortion in Burkina Faso: The interface of local norms and global public health practice Glob. Public Health 2014 9 946 959 10.1080/17441692.2014.937828 25132157 \n38. CIA World Factbook Burkina Faso Demographics Profile 2018 Available online: https://www.indexmundi.com/burkina_faso/demographics_profile.html (accessed on 28 April 2018) \n39. Bodart C. Servais G. Mohamed Y.L. Schmidt-Ehry B. The influence of health sector reform and external assistance in Burkina Faso Health Policy Plan. 2001 16 74 86 10.1093/heapol/16.1.74 11238434 \n40. Ministry of health of Burkina Faso Liste National des Medicaments et Consommables Medicaux Essentiels Ministry of health Burkina Faso, Ouagadougou 2014 \n41. Van Der Geest S. Whyte S.R. The Charm of Medicines: Metaphors and Metonyms Med. Anthr. Q. 1989 3 345 367 10.1525/maq.1989.3.4.02a00030 \n42. Leone T. Coast E. Parmar D. Vwalika B. The individual level cost of pregnancy termination in Zambia: A comparison of safe and unsafe abortion Health Policy Plan. 2016 31 825 833 10.1093/heapol/czv138 26879090 \n43. Caronia L. Mortari L. The agency of things: How spaces and artefacts organize the moral order of an intensive care unit Soc. Semiot. 2015 25 401 422 10.1080/10350330.2015.1059576 \n44. Akrich M. Comment décrire les objets techniques? Tech. Cult. 1987 9 49 64 10.4000/tc.863 \n45. Clarke A. Montini T. The Many Faces of RU486: Tales of Situated Knowledges and Technological Contestations Sci. Technol. Hum. Values 1993 18 42 78 10.1177/016224399301800104 11652075 \n46. Schnegg C. L’avortement médicamenteux: De la technique à l’expérience. La méthode abortive en question Nouv. Quest. Féministes 2007 26 60 72 10.3917/nqf.262.0060 \n47. Footman K. Keenan K. Reiss K. Reichwein B. Biswas P. Church K. Medical Abortion Provision by Pharmacies and Drug Sellers in Low-and Middle-Income Countries: A Systematic Review Stud. Fam. Plan. 2018 49 57 70 10.1111/sifp.12049 29508948 \n48. Briozzo L. Vidiella G. Rodríguez F. Gorgoroso M. Faúndes A. Pons J.E. A risk reduction strategy to prevent maternal deaths associated with unsafe abortion Int. J. Gynecol. Obstet. 2006 95 221 226 10.1016/j.ijgo.2006.07.013 17010348\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "16(22)",
"journal": "International journal of environmental research and public health",
"keywords": "Burkina Faso; abortion; ethnography; misoprostol; women",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000028:Abortion, Induced; D000293:Adolescent; D000328:Adult; D000884:Anthropology, Cultural; D002050:Burkina Faso; D005260:Female; D006297:Health Services Accessibility; D006801:Humans; D016595:Misoprostol; D011247:Pregnancy; D055815:Young Adult",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31718106",
"pubdate": "2019-11-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17010348;28964589;29357663;25636515;29104024;27179755;27008072;23433680;27382216;22789095;20561739;3514547;25132157;12972013;25103301;11652075;21530840;24790605;26879090;19286183;29508948;23684204;11238434;16076516",
"title": "A Pill in the Lifeworld of Women in Burkina Faso: Can Misoprostol Reframe the Meaning of Abortion.",
"title_normalized": "a pill in the lifeworld of women in burkina faso can misoprostol reframe the meaning of abortion"
} | [
{
"companynumb": "NO-LUPIN PHARMACEUTICALS INC.-2019-07892",
"fulfillexpeditecriteria": "2",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditiona... |
{
"abstract": "Anti-NMDAR (N-methyl-D-aspartic acid receptor) encephalitis, first described in 2007, is a rare, autoimmune limbic encephalitis. In half of the cases anti-NMDAR antibodies are paraneoplastic manifestations of an underlying tumor (mostly ovarian teratoma). In the early stage of the disease psychiatric symptoms are prominent, therefore 60-70% of the patients are first treated in a psychiatric department. In most of the cases, typical neurological symptoms appear later. Besides the clinical picture and typical symptoms, verifying presence of IgG antibodies in the serum or CSF is necessary to set up the diagnosis. Other diagnostic tools, including laboratory tests, MRI, lumbar puncture or EEG are neither specific, nor sensitive enough. Therapy is based on supportive care, plasma exchange and immune suppression, intensive care administration can be necessary. If there is an underlying tumor, tumor removal is the first-line treatment. The disease can cause fatal complications in the acute phase but with adequate therapy long-term prognosis is good, although rehabilitation can last for months. In the past few years besides the typical clinical picture and illness course an increasing number of case reports described no typical neurological symptoms, only psychiatric symptoms, including psychosis, disorganized behavior, and catatonic symptoms. Immune suppressive treatment was still effective in most of these cases. Such cases present a difficult diagnostic challenge. These patients may receive unnecessary antipsychotic treatment because of the suspected schizophrenia, although they often suffer from serious extrapyramidal side effects. A few years ago there was a hypothesis that a small part of the patients who are treated with therapy-resistant schizophrenia may suffer from anti-NMDAR encephalitis, so they require a different kind of medication. Evidence from the latest publications did not confirm this hypothesis, although the connection between anti-NMDAR antibodies and disorders with psychotic symptoms is still not clear. After reviewing the most important studies regarding the psychiatric aspects of anti-NMDAR encephalitis, we present a case report of a patient with a pure psychiatric manifestation of this disease. We conclude with a short outline of the design and plan of our future study.",
"affiliations": "Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest, Hungary. herman.levente@med.semmelweis-univ.hu.",
"authors": "Herman|Levente|L|;Zsigmond|Ildiko Reka|IR|;Peter|Laszlo|L|;Rethelyi|Janos M|JM|",
"chemical_list": "D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate",
"country": "Hungary",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1419-8711",
"issue": "18(4)",
"journal": "Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology",
"keywords": null,
"medline_ta": "Neuropsychopharmacol Hung",
"mesh_terms": "D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D006801:Humans; D020363:Limbic Encephalitis; D016202:N-Methylaspartate; D011618:Psychotic Disorders; D016194:Receptors, N-Methyl-D-Aspartate",
"nlm_unique_id": "100961631",
"other_id": null,
"pages": "199-208",
"pmc": null,
"pmid": "28259863",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Review of the psychiatric aspects of anti-NMDA (N-methyl-D-aspartic acid) receptor encephalitis, case report, and our plans for a future study.",
"title_normalized": "review of the psychiatric aspects of anti nmda n methyl d aspartic acid receptor encephalitis case report and our plans for a future study"
} | [
{
"companynumb": "HU-PFIZER INC-2019034488",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMISULPRIDE"
},
"drugadditional": null,
... |
{
"abstract": "With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.\n\n\n\nPatients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.\n\n\n\nIn total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).\n\n\n\nHem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.",
"affiliations": "Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany.;Department of Dermatology, Venerology und Allergology, University Hospital Essen, Essen, Germany.;Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Dermatology, Venerology und Allergology, University Hospital Essen, Essen, Germany.;Vanderbilt University Medical Center, Department of Medicine, Division of Hematology and Oncology, Nashville, USA.;Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.;Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.;Medical Oncology Department, Peter MacCallum Cancer Centre, Melbourne, Australia.;Medical Oncology Department, Peter MacCallum Cancer Centre, Melbourne, Australia.;Department of Dermatology, University Medical Center, Mainz, Germany.;Department of Dermatology, University Medical Center, Mainz, Germany.;Department of Dermatology, Saarland University Medical Center, Homburg/Saar, Germany.;Department of Medical Oncology, Melanoma Institute Australia, Sydney, Australia; Medical Oncology Service, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil.;Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.;Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.;Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney, NSW, Australia.;Department of Dermatology, Allergology and Phlebology, Bremerhaven Reinkenheide Hospital, Bremerhaven, Germany.;APHP, Department of Dermatology, Saint-Louis Hospital, Université de Paris, INSERM U976, Paris, France.;APHP, Department of Dermatology, Saint-Louis Hospital, Université de Paris, INSERM U976, Paris, France.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.;Department of Dermatology, Charité University Hospital, Berlin, Germany.;Department of Dermatology and Allergy, LMU, University Hospital, Munich, Germany.;Department I of Internal Medicine, Centre of Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.;Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases, Dresden, Germany; Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany.;Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases, Dresden, Germany; Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany.;Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Dermatology, University Hospital Tübingen, Germany.;Department of Dermatology, University Hospital Kiel, Kiel, Germany.;Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany.;Department of Dermatology, Venerology und Allergology, University Hospital Essen, Essen, Germany.;Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany; Department of Dermatology and Allergy, LMU, University Hospital, Munich, Germany. Electronic address: Lucie.Heinzerling@med.uni-muenchen.de.",
"authors": "Kramer|Rafaela|R|;Zaremba|Anne|A|;Moreira|Alvaro|A|;Ugurel|Selma|S|;Johnson|Douglas B|DB|;Hassel|Jessica C|JC|;Salzmann|Martin|M|;Gesierich|Anja|A|;Weppler|Alison|A|;Spain|Lavinia|L|;Loquai|Carmen|C|;Dudda|Milena|M|;Pföhler|Claudia|C|;Hepner|Adriana|A|;Long|Georgina V|GV|;Menzies|Alexander M|AM|;Carlino|Matteo S|MS|;Sachse|Michael M|MM|;Lebbé|Céleste|C|;Baroudjian|Barouyr|B|;Enokida|Tomohiro|T|;Tahara|Makoto|M|;Schlaak|Max|M|;Hayani|Kinan|K|;Bröckelmann|Paul J|PJ|;Meier|Friedegund|F|;Reinhardt|Lydia|L|;Friedlander|Philip|P|;Eigentler|Thomas|T|;Kähler|Katharina C|KC|;Berking|Carola|C|;Zimmer|Lisa|L|;Heinzerling|Lucie|L|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000082082:Immune Checkpoint Inhibitors; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2021.01.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "147()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Anaemia; Anti-CTLA-4-Antibody; Anti-PD1-Antibody; Autoimmunity; Haematotoxicity; Hemophagocytic lymphohistiocytosis; Leucopaenia; Neutropenia; Side-effects; Thrombocytopenia",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012189:Retrospective Studies; D013921:Thrombocytopenia; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "170-181",
"pmc": null,
"pmid": "33706206",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hematological immune related adverse events after treatment with immune checkpoint inhibitors.",
"title_normalized": "hematological immune related adverse events after treatment with immune checkpoint inhibitors"
} | [
{
"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-031757",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nSunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours.\n\n\nMETHODS\nWe retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice.\n\n\nRESULTS\nEight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.\n\n\nCONCLUSIONS\nLeft ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.",
"affiliations": "Department of Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.",
"authors": "Chu|Tammy F|TF|;Rupnick|Maria A|MA|;Kerkela|Risto|R|;Dallabrida|Susan M|SM|;Zurakowski|David|D|;Nguyen|Lisa|L|;Woulfe|Kathleen|K|;Pravda|Elke|E|;Cassiola|Flavia|F|;Desai|Jayesh|J|;George|Suzanne|S|;Morgan|Jeffrey A|JA|;Harris|David M|DM|;Ismail|Nesreen S|NS|;Chen|Jey-Hsin|JH|;Schoen|Frederick J|FJ|;Van den Abbeele|Annick D|AD|;Demetri|George D|GD|;Force|Thomas|T|;Chen|Ming Hui|MH|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(07)61865-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "370(9604)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000818:Animals; D000970:Antineoplastic Agents; D001794:Blood Pressure; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006333:Heart Failure; D006801:Humans; D007211:Indoles; D008297:Male; D051379:Mice; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D051381:Rats; D012189:Retrospective Studies; D013318:Stroke Volume; D000077210:Sunitinib",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "2011-9",
"pmc": null,
"pmid": "18083403",
"pubdate": "2007-12-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15711537;16446321;15459012;16446323;16652186;10482197;12538485;16168273;16330672;11248153;15609077;9811454;17332278;16892027;17046465;16862153;16880234;17457301;16407877;17215529;16014887;15623421;16757724;10561337;16314617",
"title": "Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.",
"title_normalized": "cardiotoxicity associated with tyrosine kinase inhibitor sunitinib"
} | [
{
"companynumb": "US-PFIZER INC-2017099128",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": "3",
... |
{
"abstract": "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.;Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.;Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.;Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.",
"authors": "Jimenez|Erick|E|0000-0001-6507-7007;Cortez|Daniel|D|;McGill|Mark|M|;Ambrose|Matthew|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/anec.12796",
"fulltext": "\n==== Front\nAnn Noninvasive Electrocardiol\nAnn Noninvasive Electrocardiol\n10.1111/(ISSN)1542-474X\nANEC\nAnnals of Noninvasive Electrocardiology\n1082-720X\n1542-474X\nJohn Wiley and Sons Inc. Hoboken\n\n32978983\n10.1111/anec.12796\nANEC12796\nCase Report\nCase Reports\nPeripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia\nJIMENEZ et al.\nJimenez Erick MD https://orcid.org/0000-0001-6507-7007\n1 jimen191@umn.edu\n\nCortez Daniel MD 1\nMcGill Mark MD 1\nAmbrose Matthew MD 1\n1 Division of Pediatric Cardiology Department of Pediatrics University of Minnesota Minneapolis Minnesota USA\n* Correspondence\nErick Jimenez, MD, Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, 2450 Riverside Ave 8951H (Campus Delivery Code), Minneapolis, MN 55454.\nEmail: jimen191@umn.edu\n\n26 9 2020\n3 2021\n26 2 10.1111/anec.v26.2 e1279610 6 2020\n07 8 2020\n08 8 2020\n© 2020 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.\n\narrhythmia\nbeta‐blockers\npalpitations\npregnancy\nventricular tachycardia\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:05.03.2021\nJimenez E , Cortez D , McGill M , Ambrose M . Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia. Ann Noninvasive Electrocardiol.2021;26 :e12796. 10.1111/anec.12796\n==== Body\n1 CASE REPORT\n\nA 28‐year‐old female, with her third pregnancy (one completed to term and one spontaneous abortion with unknown cause) at 39 weeks of gestational age and with a history of CPVT type 1 (pathological mutation c.506G > A in the ryanodine receptor [RYR2] gene) (Hsueh, Weng, & Chen, 2006), underwent secondary prevention single‐chamber, single‐coil Boston Scientific Energen implantable cardioverter defibrillator (ICD) placement after she had a sudden cardiac arrest at 23 years of age. The cardiac arrest occurred while the patient was driving, and she was found to be in ventricular tachyarrhythmia by the police. At that point, etiology of the arrest had not been determined and genetic testing had not been performed due to cost limitations.\n\nOf note, the patient's first pregnancy and vaginal delivery occurred prior to her episode of sudden cardiac arrest. These events were uncomplicated and resulted in a child who had sudden cardiac death at 2 years of age (previously asymptomatic); autopsy did not show any abnormalities and DNA testing diagnosed CPVT due to a RyR2 mutation. This eventually led to the genetic evaluation and diagnosis in our patient.\n\nOur patient presented at 23 weeks of gestational age for a fetal cardiology evaluation. She was asymptomatic, except for occasional lower extremities edema. Her cardiovascular examination was normal. She was taking metoprolol 25 mg daily and flecainide 50 mg twice daily before, and it was continued throughout the entire pregnancy. Her ICD was programmed with VVI pacing at 35 bpm, with a ventricular tachycardia (VT) monitor zone at 190 bpm and only one therapy zone of a ventricular fibrillation (VF) zone at 240bpm (anti‐tachycardia pacing [ATP] only during charge, then shock). Her fetal echocardiography was normal. During follow‐up, interrogation of ICD showed no history of ATP or shock therapy delivered. It also demonstrated 3 episodes of non‐sustained VT (NSVT) (9–18 s at rates of 217–254 bpm) in the first trimester. Episodes of NSVT became more frequent (about once a week from 29 to 33 WGA) and she remained asymptomatic during these events. ICD settings and medications doses were kept unchanged throughout the pregnancy. Given the episodes of NSVT, the metoprolol was increased to 25 mg twice daily.\n\nA multidisciplinary meeting, attended by maternal fetal medicine, cardiology (general, fetal, and electrophysiology), anesthesiology, intensive care (cardiovascular [CVICU] and neonatal [NICU]), and social work, was held to discuss the case. It was agreed to have a route and timing of delivery based on the usual indications, with follow‐up by maternal fetal medicine every 2 weeks until 36 WGA, then weekly thereafter. Serial ultrasound assessment to monitor fetal growth and a repeated fetal echocardiogram was scheduled at 30 WGA.\n\nFor labor and delivery, the plan was arranged as follows: Care team huddle to ensure all team members were in agreement with the management plan.\n\nCollect cord blood sample for genetic testing for CPVT (RyR2).\n\nNewborn to be monitored in the NICU for risk of arrhythmia and hypoglycemia. Mother opted for breastfeeding to provide beta‐blockade to the newborn, understanding this may be suboptimal.\n\nEarly epidural anesthesia and prophylactic dexmedetomidine were recommended for sympathetic suppression.\n\nContinuous cardiovascular monitoring.\n\nAvoidance of sympathomimetics (i.e., terbutaline, epinephrine, and methergine) for the usual labor indications; phenylephrine was the recommended vasopressor if needed.\n\nElectrolytes goal: magnesium >2 mg/dl, ionized calcium >4.5 mg/dl, and potassium >3.5 mg/dl. This was to prevent confounding causes of ventricular ectopy.\n\nEsmolol infusion to be initiated depending on the last dose of metoprolol and ectopic burden.\n\nFlecainide to be continued as scheduled and additional doses could be considered for increased ectopic burden.\n\nICD lower ventricular pacing rate adjustment to improve rate regulation (pacing at higher rates).\n\nIf surgical delivery, ICD shock setting should be turned off to avoid possible inappropriate therapy delivery secondary to cauterizer. If so, external defibrillator pads should be placed.\n\nMaintain open communication with the patient throughout labor to promote the least possible stressful environment.\n\nTwo CVICU nurses to provide collaborative care during labor and delivery.\n\nShe was admitted at 39 weeks of gestational age for induction of labor. Her ICD interrogation showed two episodes of NSVT in the week prior to admission. During labor, an epidural with bupivacaine was placed, sympathomimetic medication was avoided, and infusions of dexmedetomidine at 0.1 mcg/kg/min and esmolol at 50 mcg/kg/min were started. Given increased polymorphic PVC burden (bigeminy), esmolol was up‐titrated to 150 mcg/kg/min and the ventricular pacing rate was increased to 100 bpm resulting in suppression of ectopy (Figure 1). She delivered a 2608 g female without complications. Esmolol and dexmedetomidine infusions were gradually weaned off within the next 12 hr after metoprolol was restarted. Ventricular pacing was set to baseline configurations 24 hr postpartum. Neonate was observed in the NICU for 48 hr without symptoms. Genetic testing from cord blood was obtained, and results were negative for the maternal mutation.\n\nFigure 1 PVC burden. a, Premature ventricular contractions (PVC) with trigeminy pattern. b, Histogram with decreasing PVC burden after increasing esmolol dose\n\n2 DISCUSSION\n\nCatecholaminergic polymorphic ventricular tachycardia is a rare inherited rhythm disorder with an estimated prevalence of about 0.1 per 1,000 people. It could be associated with autosomal dominant transmission (RyR2 gene mutation, CPVT 1) or autosomal recessive transmission (CASQ2 gene mutation, CPVT 2) (Priori, Wilde, & Horie, 2013). This channelopathy is caused by a mutation that provokes excessive intramyocardial calcium release in the setting of a catecholamine surge, and presents with ventricular tachycardia/fibrillation during exercise or emotional stress that can variably manifest from palpitations to sudden death. Pregnancy induces several hormonal, physiologic, and autonomic changes, including increased cardiovascular response to circulating catecholamines (Barron, Mujais, Zinaman, Bravo, & Lindheimer, 1986), and the peripartum is a stage that carries a significant amount of emotional and physical stress.\n\nThere is very limited literature regarding the management of patients with CPVT during the peripartum period. Our literature search found only four case reports describing their experience with labor and delivery in patients with polymorphic VT (Ahmed & Phillips, 2016; Burrows, Fox, Biblo, & Roth, 2013; Friday, Moak, Fries, & Iqbal, 2015; Gogle & Kemp, 2018). Given that this is a rare clinical scenario, and there are a lack of guidelines for its management, approaches have varied within all cases reported, including a clinical dilemma about the need to treat or not to treat an asymptomatic patient (Kotschet, Hunter, Kroushev, & Wallace, 2017).\n\nAlthough there are conflicting data about the amount of catecholaminergic surge in vaginal versus cesarean delivery, research has shown that maternal levels of catecholamines are higher during vaginal delivery compared with cesarean section (Irestedt, Lagercrantz, Hjemdahl, Hagnevik, & Belfrage, 1982); however, the combined pregnancy and postpartum arrhythmic risk in CPVT patients may not be elevated compared with the nonpregnant period (Cheung, Lieve, & Roston, 2019; Roston, van der Werf, & Cheung, 2020). It is known that epidural anesthesia during labor reduces maternal catecholamine levels, probably by eliminating the psychological and physical stress associated with painful uterine contractions (Shnider et al., 1983), reason why our management included early application of this therapy.\n\nOur case presented with a previous history of uncomplicated vaginal delivery that occurred before her cardiac arrest. Although not hemodynamically significant, there was an increase in the frequency of NSVT toward the end of the pregnancy and this was more noticeable during the labor, despite early epidural anesthesia and sympathetic suppression. This increment in her ectopic burden improved after beta‐blockade increase and adjustment of the ventricular pacing rate.\n\n3 CONCLUSION\n\nDefining a clear multidisciplinary plan, including anticipated escalation of care for possible complications, helped provide an effective approach to treat this unusual situation on a rare condition and created a level of familiarity among the care providers that certainly contributed to deliver a safer and less stressful experience for both, patient and providers.\n\nCONFLICT OF INTEREST\n\nThe authors declare that there are no relevant or material financial interests that relate to disclose.\n\nAUTHOR CONTRIBUTION\n\nAll authors participated in writing and editing the manuscript.\n\nETHICS\n\nThe Institutional Review Board of the University of Minnesota waived the need for ethics approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this non‐interventional study.\n==== Refs\nREFERENCES\n\nAhmed, A. , & Phillips, J. R. (2016). Teenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented ICD discharges Key Clinical Message. Clinical Case Reports, 4 (4 ), 361–365. 10.1002/ccr3.366 27099728\nBarron, W. M. , Mujais, S. K. , Zinaman, M. , Bravo, E. L. , & Lindheimer, M. D. (1986). Plasma catecholamine responses to physiologic stimuli in normal human pregnancy. American Journal of Obstetrics and Gynecology, 154 (1 ), 80–84. 10.1016/0002-9378(86)90397-2 3511708\nBurrows, K. , Fox, J. , Biblo, L. A. , & Roth, J. A. (2013). Pregnancy and short‐coupled torsades de pointes. PACE ‐ Pacing and Clinical Electrophysiology, 36 (3 ), e77–e79. 10.1111/j.1540-8159.2010.02923.x 21039642\nCheung, C. C. , Lieve, K. V. , Roston, T. M. , van der Ree, M. H. , Deyell, M. W. , Andrade, J. G. , … Krahn, A. D. (2019). Pregnancy in catecholaminergic polymorphic ventricular tachycardia. JACC Clinical Electrophysiology, 5 (3 ), 387–394. 10.1016/j.jacep.2018.10.019 30898243\nFriday, K. P. , Moak, J. P. , Fries, M. H. , & Iqbal, S. N. (2015). Catecholaminergic ventricular tachycardia, pregnancy and teenager: Are they compatible? Pediatric Cardiology, 36 (7 ), 1542–1547. 10.1007/s00246-015-1232-3 26278400\nGogle, J. , & Kemp, T. L. (2018). Use of interprofessional simulation to prepare for the cardiac emergency of catecholaminergic polymorphic ventricular tachycardia during pregnancy. Journal of Obstetric, Gynecologic, and Neonatal Nursing, 47 (3 ), S66. 10.1016/j.jogn.2018.04.129\nHsueh, C. H. , Weng, Y. C. , Chen, C. Y. , Lin, T. K. , Lin, Y. H. , Lai, L. P. , & Lin, J. L. (2006). A novel mutation (Arg169Gln) of the cardiac ryanodine receptor gene causing exercise‐induced bidirectional ventricular tachycardia. International Journal of Cardiology, 108 (2 ), 276–278. 10.1016/j.ijcard.2005.02.051 16517285\nIrestedt, L. , Lagercrantz, H. , Hjemdahl, P. , Hagnevik, K. , & Belfrage, P. (1982). Fetal and maternal plasma catecholamine levels at elective cesarean section under general or epidural anesthesia versus vaginal delivery. American Journal of Obstetrics and Gynecology, 142 (8 ), 1004–1010. 10.1016/0002-9378(82)90783-9 7072768\nKotschet, E. , Hunter, M. , Kroushev, A. , & Wallace, E. (2017). To treat or not to treat: A therapeutic dilemma in a gene positive, phenotypic negative CPVT woman throughout her pregnancies. Heart, Lung and Circulation, 26 , S308. 10.1016/j.hlc.2017.06.612\nPriori, S. G. , Wilde, A. A. , Horie, M. , Cho, Y. , Behr, E. R. , Berul, C. , … Tracy, C. (2013). HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm, 10 (12 ), 1932–1963. 10.1016/j.hrthm.2013.05.014 24011539\nRoston, T. M. , van der Werf, C. , Cheung, C. C. , Grewal, J. , Davies, B. , Wilde, A. A. M. , & Krahn, A. D. (2020). Caring for the pregnant woman with an inherited arrhythmia syndrome. Heart Rhythm, 17 (2 ), 341–348. 10.1016/j.hrthm.2019.08.004 31400520\nShnider, S. M. , Abboud, T. K. , Artal, R. , Henriksen, E. H. , Stefani, S. J. , & Levinson, G. (1983). Maternal catecholamines decrease during labor after lumbar epidural anesthesia. American Journal of Obstetrics and Gynecology, 147 (1 ), 13–15. 10.1016/0002-9378(83)90076-5 6614080\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1082-720X",
"issue": "26(2)",
"journal": "Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc",
"keywords": "arrhythmia; beta-blockers; palpitations; pregnancy; ventricular tachycardia",
"medline_ta": "Ann Noninvasive Electrocardiol",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D017147:Defibrillators, Implantable; D036861:Delivery, Obstetric; D004562:Electrocardiography; D005260:Female; D006801:Humans; D058725:Peripartum Period; D011247:Pregnancy; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome",
"nlm_unique_id": "9607443",
"other_id": null,
"pages": "e12796",
"pmc": null,
"pmid": "32978983",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "16517285;24011539;3511708;31400520;26278400;30898243;6614080;7072768;27099728;32978983;21039642",
"title": "Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia.",
"title_normalized": "peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-215770",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLECAINIDE ACETATE"
},
... |
{
"abstract": "OBJECTIVE\nTo report 2 cases of corneal perforation associated with the use of oral nonsteroidal anti-inflammatory drugs (NSAIDs).\n\n\nMETHODS\nIn a 62-year-old woman and a 79-year-old woman, corneal perforation occurred after 7 days and 5 months of oral NSAIDs administration, respectively.\n\n\nRESULTS\nAfter NSAIDs were discontinued, the cornea epithelialized and the anterior chamber formed within 14 and 10 days, respectively.\n\n\nCONCLUSIONS\nIt is well known that topical NSAIDs cause corneal perforation. Observations in the present cases suggest that the oral administration of NSAIDs may also cause corneal damage, and hence, medical professionals should consider the risk of damage to the cornea when administering these drugs orally.",
"affiliations": "Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. masuda-i@cc.okayama-u.ac.jp",
"authors": "Masuda|Ikuya|I|;Matsuo|Toshihiko|T|;Okamoto|Kazuo|K|;Matsushita|Kyoko|K|;Ohtsuki|Hiroshi|H|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "United States",
"delete": false,
"doi": "10.1177/112067211002000230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "20(2)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001172:Arthritis, Rheumatoid; D003315:Cornea; D057112:Corneal Perforation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease; D014945:Wound Healing",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "454-6",
"pmc": null,
"pmid": "20037896",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of corneal perforation after oral administration of nonsteroidal anti-inflammatory drugs: oral NSAID-induced corneal damage.",
"title_normalized": "two cases of corneal perforation after oral administration of nonsteroidal anti inflammatory drugs oral nsaid induced corneal damage"
} | [
{
"companynumb": "JP-BAUSCH-BL-2020-018005",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients. Neuroleptic malign syndrome (NMS) is an idiosyncratic drug reaction showing fever, dysautonomia and rigidity with increased levels of Creatinine-phosphokinase (CPK) dependent on leakage of muscle contents into the circulation and defined as rhabdomyolysis. Although different diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur, particularly during treatment with atypical antipsychotics. We here present a case report of a psychiatric patient affected by a SIADH complicated with NMS/rhabdomyolysis, induced by second-generation (atypical) antipsychotic drugs in combination with carbamazepine and promazine.",
"affiliations": "1U.O.C di Medicina Generale e Lungodegenza.;U.O.C. di Patologia Generale Ospedale San Giovanni Bosco, ASL Na1-Centro, Naples, Italy.;1U.O.C di Medicina Generale e Lungodegenza.",
"authors": "Bassi|V|V|;Fattoruso|O|O|;Santinelli|C|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omz010",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omz010omz010Case ReportA rare iatrogenic association of syndrome of inappropriate secretion of antidiuretic hormone, neuroleptic malignant syndrome and rhabdomyolysis Bassi V 1Fattoruso O 2Santinelli C 11 1U.O.C di Medicina Generale e Lungodegenza2 U.O.C. di Patologia Generale Ospedale San Giovanni Bosco, ASL Na1-Centro, Naples, ItalyCorrespondence address. Via Petrarca 74, 80122 Naples, Italy. Tel:+390815562981 E-mail: dr_bassi@inwind.it3 2019 29 3 2019 29 3 2019 2019 3 omz01023 7 2018 28 12 2018 07 2 2019 © The Author(s) 2019. Published by Oxford University Press.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nSyndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients. Neuroleptic malign syndrome (NMS) is an idiosyncratic drug reaction showing fever, dysautonomia and rigidity with increased levels of Creatinine-phosphokinase (CPK) dependent on leakage of muscle contents into the circulation and defined as rhabdomyolysis. Although different diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur, particularly during treatment with atypical antipsychotics. We here present a case report of a psychiatric patient affected by a SIADH complicated with NMS/rhabdomyolysis, induced by second-generation (atypical) antipsychotic drugs in combination with carbamazepine and promazine.\n==== Body\nINTRODUCTION\nSyndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered the prevalent cause of hyponatremia in hospitalized patients [1]. Neuroleptic malignant syndrome (NMS) is an idiosyncratic drug reaction showing fever, dysautonomia and rigidity with increased levels of creatinine-phosphokinase (CPK), dependent on leakage of muscle contents into the circulation and defined as rhabdomyolysis [2]. Although different diagnostic criteria for NMS have been established, it should be recognized that atypical presentations can occur, particularly during treatment with atypical antipsychotics [3]. We present a case report of a psychiatric patient affected by a SIADH complicated with NMS/rhabdomyolysis induced by an oral therapy of atypical antipsychotic drugs in combination with carbamazepine and promazine. The patient had a medical history of ten years bipolar disorder and, recently, his psychiatrist increased the promazine dosage.\n\nAll antipsychotic drugs are associated with adverse events such as sedation, cardiac arrhythmia, postural hypotension, sexual dysfunction and sudden cardiac death [4]. Moreover, the antipsychotic drugs are involved in all the three potentially life-threatening events, such as syndrome of inappropriate antidiuretic hormone secretion, NMS and rhabdomyolysis. The second-generation antipsychotics were initially assumed to be free from the risk of inducing NMS because of their more favorable pharmacodynamic profile. The post-marketing studies have confirmed that also these drugs possess a reduced, but still present, risk of NMS complication [3, 5].\n\nAnyway, the association between SIADH and NMS is an infrequent finding [6] while the coexistence of three different adverse effects such as SIADH, NMS and rhabdomyolysis is described only in two cases following oral sulpiride or parenteral paliperidone therapy [7, 8].\n\nWe report a very unusual case of the coexistence of SIADH/NMS/rhabdomyolysis following an oral polytherapy in a psychiatric patient.\n\nCASE PRESENTATION\nA 56-year-old Caucasian male presented to the Emergency Department of our Hospital with a four days history of altered consciousness level, hyperpyrexia (38.7°C), tachypnea (32 breathes/m), tachycardia, profound diaphoresis, myalgia and severe muscle weakness. The relatives referred a medical history of type 2 diabetes mellitus (metformin 500 mg three times a day) and bipolar disorder, treated with antipsychotic drugs (paliperidone 3 mg once a day, olanzapine 10 mg once a day), carbamazepine 400 mg twice a day and promazine hydrochloride 90 mg twice a day. He has been under the actual drug therapy for 24 months when, 10 days before the hospital admission, the promazine dose was increased (from 60 to 90 mg twice a day) to achieve a better control of the anxiety. Three months before the hospital admission, routine blood laboratory parameters, including serum transaminases, blood urea nitrogen, creatinine, sodium, potassium, CPK and carbamazepine level, were in the normal range.\n\nAt the admission, the relatives denied seizures, polydipsia, nausea, vomiting, diarrhea or a recent use of diuretics while the fever started two days before. The blood pressure was fluctuating between values of 140/80 and 170/95 mmHg with a sinus heart rate fluctuating between 79 and 118 beats/min and a 39.6°C oral temperature upon admission. The chest, heart, abdominal and neurologic exams were normal without nuchal rigidity or meningeal signs. A mild muscle rigidity was present while the patient presented a severe weakness. The findings of normal skin turgor, moist mucous membranes and the absence of orthostatic hypotension, jugular vein engorgement and edema suggested an euvolemic status. The laboratory parameters (Table 1) associated with normal cardiac and endocrine function suggested a diagnosis of SIADH associated to NMS complicated with rhabdomyolysis. The anamnestic history and radiological investigations, such as a total-body computed tomography failed to identify other possible causes of SIADH. A water load test (0.9% NaCl solution 2 l in 24 h) did not modify significantly the serum Na levels (from 121 mEq/l to 123 mEq/l).\nTable 1: Laboratory parameters on different days\n\nr. r.\tsNa\tuNa\tP. Osm\tU.A\tCr.\tBUN\tsCPK/myoglobin\tU. Osm\tFENa\tFEUA\t\nDAYS\t135–145 mEq/l\t40–220 mEq/l\t275–285 mOsm/kg\t2.4–5.7 mg/dl\t0.5–0.9 mg/dl\t10–50 mg/dl\t250–500/20–80 mg/dl, ng/ml\t50–1200 mOsm/kg\t0.1–0.5%\t5–12%\t\n1\t121\t\t\t\t1.2\t43\t\t\t\t\t\n2\t123\t51\t252\t7.8\t1.5\t65\t35 327/-\t\t\t4.8\t\n3\t125\t78\t256\t4.0\t0.9\t39\t41 558/-\t352\t0.54\t12.9\t\n4\t129\t\t\t\t\t\t33 921/1701\t\t\t\t\n5\t139\t\t\t\t\t\t\t\t\t\t\n6\t145\t\t\t\t\t\t15 567/518\t\t\t\t\n7\t141\t\t\t3.4\t0.7\t24\t1388/160\t\t\t\t\n14\t144\t\t\t3.2\t0.7\t28\t445/50\t\t\t5.5\t\nGray row: SIADH diagnosis was made and tolvaptan therapy was started.\n\nr.r.: reference range, sNa: serum sodium, uNa: urine sodium, P. Osm: plasma osmolality, U.A.: serum uric acid, Cr.: serum creatinine, BUN: blood urea nitrogen, sCPK: serum creatine phosphokinase, U. Osm.: urine osmolality, FENa: sodium fraction excretion, FEUA: uric ucid fraction excretion.\n\n\n\nAntipsychotic drugs were stopped and a 1.5% hypertonic NaCl solution (containing Na 255 mEq/l), a 1.4% bicarbonate solution (Na 167 mEq/l) and fluid hydration (0.9% saline 4 l/day) were started. The 1.5% NaCl and bicarbonate solutions were continued until the third day obtaining a serum value of 125 mEq/l with the resolution of the fever. Then, SIADH diagnosis was made and tolvaptan therapy (15 mg/day) started, decreasing the hydration regimen to 2.5 l/day. On the fifth day, after three days of tolvaptan therapy, serum Na level was 139 mEq/ml and a normal mental status was restored, then tolvaptan was stopped and the antipsychotic therapy was resumed (paliperidone 3 mg once a day and carbamazepine 100 mg twice a day, lorazepam 2 mg once a day) in consideration of the onset of agitation and irritability. Unfortunately, we could not measure the different drug levels due to the lacking of specific assay kits. On the 7th day, the patient was discharged presenting 141 mEq/l Na, 1388 mg/dl CPK and 160 ng/ml myoglobin, scheduling a weekly follow-up. Hyponatremia, NMS and rhabdomyolysis did not relapse at subsequent monthly follow-up, up to 1 year.\n\nDISCUSSION\nThe investigated patient presented a medical history, clinical symptoms and laboratory values consistent with SIADH diagnosis, complicated by rhabdomyolysis and symptoms of an unregulated sympathetic nervous system hyperactivity suggesting a NMS presenting only a mild muscular rigidity. NMS is a diagnosis of exclusion and differential diagnosis relies on four major criteria: hyperthermia, rigidity, autonomic disturbances and mental status changes. Usually, DSM 5 criteria exclude a ‘classic’ NMS in the absence of severe muscular rigidity. Anyway, other classifications, such as Adityanjee & Aderibigbe criteria, take into consideration ‘atypical’ forms of NMS where extrapyramidal signs are not strictly necessary. Moreover, also the traditional Levenson’s criteria stated that the association of two major criteria (present in our patient) such as fever >38.0 °C and increased serum CPK levels with at least four minor criteria (altered consciousness level, dysautonomia, tachypnea and labile arterial pressure) suggests NMS diagnosis, also if a frank muscular rigidity was not present [9]. The second-generation antipsychotic drugs such as paliperidone and olanzapine, despite reducing the overall incidence of the syndrome, could induce atypical NMS forms, sometimes difficult to diagnose [5].\n\nIn our case study, the promazine dosage was increased but this drug could explain the onset of NMS while SIADH is not typically described as one of its side effects. Moreover, a potential role of the chronic carbamazepine therapy in the SIADH onset is possible. Our patient showed on hospital admission the level of Na serum at its nadir while CPK level was steadily increasing, suggesting that SIADH was antecedent to rhabdomyolysis/NMS appearance. Thus, severe hyponatremia could represent the trigger event of both rhabdomyolysis and NMS [9, 10]. The mechanism of muscle fibers myolysis in SIADH is dependent on cell swelling and/or the imbalance of cellular Na/K pumps increasing the intracellular calcium levels with lysis of the cells [11]. Anyway it is impossible to identify the role of a single drug in this complex clinical picture. Probably, promazine triggered the toxicity of the therapy inducing first and foremost NMS and SIADH while the severe hyponatremia was responsible of the intense rhabdomyolysis. At present, the relationship between SIADH and NMS is unknown. Common neuroanatomical areas, such as the basal ganglia, the cerebral cortex and the hypothalamic region are usually involved in both NMS and demyelinating lesions dependent on overcorrection of hyponatremia [12]. Normally, the monoamine transporters are involved in the Na/Cl-dependent reuptake of the catecholamine to regulate the extracellular monoamine concentrations. Thus, the imbalance of sodium, could determine an altered norepinephrine/dopamine ratio in these cerebral areas increasing the NMS risk in SIADH [13]. Furthermore, acute kidney failure is a harmful complication of rhabdomyolysis, complicating 30% of the cases but not found in our patient. The fluid hydration and urinary alkalinisation are indicated as the mainstay of therapy to preserve the kidney function and the intense water diuresis induced by tolvaptan could have a preserving role of the glomerular filtration. A further point of discussion is that SIADH has to be considered a challenging diagnosis when rhabdomyolysis is concomitant, since the increased levels of blood urea nitrogen, creatinine and uric acid could be misleading. In our case, the criteria of SIADH diagnosis were met only on the third day.\n\nIn conclusion, our case report gives evidence against the multiple psychiatric therapies not according to accepted medical standards and the false sense of safety of the oral vs. parenteral therapy. The physicians need to be aware of rare but life-threatening harmful side effects such as SIADH, NMS and rhabdomyolysis, also using the second-generation antipsychotic drugs, mainly in combination with other central nervous system drugs.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nUpadhyay A , Jaber BL , Madias NE \nEpidemiology of hyponatremia . Semin Nephrol 2009 ;29 :227 –38 .19523571 \n2 \nCarbone JR \nThe neuroleptic malignant and serotonin syndromes . Emerg Med Clin North Am 2000 ;18 :317 –25 .10767887 \n3 \nBhuvaneswar CG , Baldessarini RJ , Harsh VL , Alpert JE \nAdverse endocrine and metabolic effects of psychotropic drugs: selective clinical review . CNS Drugs 2009 ;23 :1003 –21 .19958039 \n4 \nMuench J , Hamer AM \nAdverse effects of antipsychotic therapy . Am Fam Physician 2010 ;81 :617 –22 .20187598 \n5 \nBelvederi Murri M , Guaglianone A , Bugliani M , Calcagno P , Respino M , Serafini G , et al \nSecond-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis . Drugs R D 2015 ;15 :45 –62 .25578944 \n6 \nGarcía Escrig M , Bermejo Pareja F , Soto Téllez O , Díaz Guzmán J , Lledó A \nNeuroleptic malignant syndrome associated with the inadequate antidiuretic hormone secretion syndrome . Arch Neurobiol (Madr) 1992 ;55 :75 –78 .1352098 \n7 \nYamaguchi K , Takamoto K , Yagi K , Tanabe H \nNeuroleptic malignant syndrome associated with the syndrome of inappropriate secretion of antidiuretic hormone . Rinsho Shinkeigaku 1995 ;35 :180 –83 .7781236 \n8 \nKaur J , Kumar D , Alfishawy M , Lopez R , Sachmechi I \nPaliperidone inducing concomitantly syndrome of inappropriate antidiuretic hormone, neuroleptic malignant syndrome, and rhabdomyolysis . Case Rep Crit Care 2016 :123 –26 .\n9 \nTrimarchi H , Gonzalez J , Olivero J \nHyponatremia associated rhabdomyolysis . Nephron 1999 ;82 :274 –77 .10396001 \n10 \nWedzicha JA , Hoffbrand BI \nNeuroleptic malignant syndrome and hyponatremia . Lancet 1984 :963 –69 .\n11 \nTing JYS \nRhabdomyolysis and polydipsic hyponatremia . Emerg Med J 2001 ;18 :art.520 .\n12 \nArieff AI , Ayus AC \nPathogenesis of hyponatremic encephalopathy, Current concepts . Chest 1993 ;103 :607 –10 .8432163 \n13 \nWeiner N , Molinof PB \nCatecholamines. Basic Neurochemistry . New York : Raven Press , 1989 , 233 –51 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2019(3)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "omz010",
"pmc": null,
"pmid": "30949348",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": "10396001;10767887;11696527;1352098;19523571;19958039;20187598;25578944;27721999;6143898;7781236;8432163",
"title": "A rare iatrogenic association of syndrome of inappropriate secretion of antidiuretic hormone, neuroleptic malignant syndrome and rhabdomyolysis.",
"title_normalized": "a rare iatrogenic association of syndrome of inappropriate secretion of antidiuretic hormone neuroleptic malignant syndrome and rhabdomyolysis"
} | [
{
"companynumb": "NVSC2020IT149448",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nIn this case report, we present an 83-year-old Caucasian immune-competent woman with Alzheimer's disease and organic personality disorder who developed auditory hallucinations when treated with two nitrofurantoin (NF) tablets (100 mg) every 12 h because of acute cystitis due to extended-spectrum-β-lactamase-positive Escherichia coli. An 83-year-old Caucasian woman with Alzheimer's disease developed auditory hallucinations 2 days after intake of two NF tablets (100 mg) daily. After thorough discussion, it was decided not to rechallenge with NF because of the serious adverse effect. After NF discontinuation suggested by clinical pharmacist and switching to imipenem 500 mg and cilastatin 500 mg three times daily for 7 days, symptoms significantly improved the next day. No other drugs known to interact with NF were administered.\n\n\nCONCLUSIONS\nNF-induced adverse effects have been reported frequently, but NF-induced auditory hallucinations with early onset in an immune-competent geriatric patient, without previous reported hallucinations or seizures, have not been reported in the literature. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between auditory hallucinations and NF use in our patient (6 points). The exact mechanism for the central nervous system (CNS) toxicity of NF in this patient is not known, but we believe that the CNS penetration of NF may result in the accumulation of toxic drug levels in CNS.\n\n\nCONCLUSIONS\nThis case report can be used to remind clinicians and clinical pharmacists of keeping in mind the potential of NF associated with auditory hallucinations, which can be easily confused with more serious conditions.",
"affiliations": "Department for Clinical Pharmacy, Psychiatric Hospital Ormoz, Ptujska Cesta 33, Ormoz, Slovenia, matejstuhec@gmail.com.",
"authors": "Štuhec|Matej|M|",
"chemical_list": "D009582:Nitrofurantoin",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-014-0577-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-5325",
"issue": "126(17-18)",
"journal": "Wiener klinische Wochenschrift",
"keywords": null,
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D005260:Female; D006212:Hallucinations; D006801:Humans; D009582:Nitrofurantoin; D016896:Treatment Outcome",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "549-52",
"pmc": null,
"pmid": "25123143",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "7249508;20227033;12522750;22376048;20512992;21450179;24268951;22850815;18495029;20981588;24199788;21292654",
"title": "Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature.",
"title_normalized": "auditory hallucinations associated with nitrofurantoin use case report and review of the literature"
} | [
{
"companynumb": "SI-ALVOGEN-2014AL001399",
"fulfillexpeditecriteria": "2",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "Eosinophilic meningitis is classically caused by Angiostrongylus cantonensis. Treatment usually includes supportive care and corticosteroids. Anthelminthic drugs are often avoided because of the risk of an inflammatory reaction to dying larvae. The duration of symptoms in most cases is up to a few weeks. We describe a case of eosinophilic meningitis, likely due to Angiostrongylus spp. infection, with recurrent symptoms and persistent cerebrospinal fluid eosinophilia despite corticosteroid treatment, over a period of almost 5 months. This only resolved after treatment with albendazole.",
"affiliations": "Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.;Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.;Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.",
"authors": "Mansbridge|Christopher T|CT|;Norton|Nicholas J|NJ|;Fox|Simon M|SM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.20-1018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": null,
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": null,
"nlm_unique_id": "0370507",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33236700",
"pubdate": "2020-11-23",
"publication_types": "D016428:Journal Article",
"references": "6591910;18922484;29210355;21524976;11870244;17177056;15306715;21923262;11017811;19706911;12637136;24583335;11498063;16114775;19366917;30454904",
"title": "Case Report: Protracted Eosinophilic Meningitis due to Probable Angiostrongyliasis.",
"title_normalized": "case report protracted eosinophilic meningitis due to probable angiostrongyliasis"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1944035",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Transdermal delivery is an alternative to oral routes of drug administration and has made considerable contributions to the treatment of various medical diseases. With the advent of new transdermal delivery technologies, higher numbers of medications are being approved for use as transdermal formulations. This route of administration has several innate advantages that have the potential to benefit various patient populations, including those with central nervous system disorders. The current review briefly outlines the history of transdermal medications, discusses the advantages and disadvantages of transdermal formulations, and examines the challenges and opportunities present for the use of transdermal treatments in psychiatry. Patients with psychiatric illnesses have many unmet needs that may be filled through the benefits gained from transdermal treatments, such as reduced dosing frequency, effective control of plasma medication concentrations, improved tolerability, ability to check compliance visually, and avoidance of first-pass hepatic metabolism. Established transdermal treatments for various psychiatric diseases are discussed followed by an introduction to therapies that are being developed as the first patch formulations for the treatment of schizophrenia. Hypothetical schizophrenia patient profiles are also outlined to aid providers in considering how transdermal treatments for this disease may fill unmet needs for specific patients. The evidence demonstrating the potential benefits of transdermal treatments in psychiatry presented in the current review should both encourage health care providers to consider how patients may benefit from transdermal alternatives and promote future innovation in the area of transdermal drug delivery for psychiatric disorders.",
"affiliations": "11 Medical Park Drive, Ste 106, Pomona, NY 10970. citrome@cnsconsultant.com.;Research and Development, Noven Pharmaceuticals, Inc, Jersey City, New Jersey, USA.;Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA.",
"authors": "Citrome|Leslie|L|;Zeni|Courtney M|CM|;Correll|Christoph U|CU|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "80(4)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000279:Administration, Cutaneous; D006801:Humans; D001523:Mental Disorders; D011619:Psychotropic Drugs; D057968:Transdermal Patch",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31318185",
"pubdate": "2019-07-16",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Patches: Established and Emerging Transdermal Treatments in Psychiatry.",
"title_normalized": "patches established and emerging transdermal treatments in psychiatry"
} | [
{
"companynumb": "US-OTSUKA-2020_005497",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "In cases showing organizing pneumonia (OP) with radiologic findings and pathological images, it is necessary to differentiate between idiopathic and secondary diseases as the cause of OP. Cryptococcus infection as a cause of OP is not well known. We herein report two cases of secondary pulmonary cryptococcosis in immunocompromised patients who showed OP, and the usefulness of bronchoscopy and serum cryptococcal antigen test for an early diagnosis. Common to both cases was that antibiotic therapy and corticosteroid therapy were ineffective, while antifungal agents were effective. In cases of immunocompromised patients who present OP with radiologic findings or pathological images, prompt administration of antifungal treatment at an early stage is important when pulmonary cryptococcosis is identified by bronchoscopy and serum cryptococcal antigen test.",
"affiliations": "Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Department of Pathology, National Hospital Organization Kanmon Medical Center, 1-1 Chofusotouracho, Shimonoseki, Yamaguchi 752-8510, Japan.;Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.",
"authors": "Chikumoto|Ayumi|A|;Oishi|Keiji|K|;Hamada|Kazuki|K|;Matsuda|Kazuki|K|;Uehara|Sho|S|;Suetake|Ryo|R|;Yamaji|Yoshikazu|Y|;Asami-Noyama|Maki|M|;Edakuni|Nobutaka|N|;Hirano|Tsunahiko|T|;Murakami|Tomoyuki|T|;Matsunaga|Kazuto|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2019.100851",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30102-910.1016/j.rmcr.2019.100851100851ArticleCryptococcosis as a cause of organizing pneumonia Chikumoto Ayumi aOishi Keiji ohishk@yamaguchi-u.ac.jpb∗Hamada Kazuki aMatsuda Kazuki aUehara Sho aSuetake Ryo aYamaji Yoshikazu aAsami-Noyama Maki aEdakuni Nobutaka aHirano Tsunahiko aMurakami Tomoyuki cMatsunaga Kazuto aa Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japanb Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japanc Department of Pathology, National Hospital Organization Kanmon Medical Center, 1-1 Chofusotouracho, Shimonoseki, Yamaguchi 752-8510, Japan∗ Corresponding author. Tel.: +81 836 22 2248; fax: +81 836 22 2246. ohishk@yamaguchi-u.ac.jp02 5 2019 2019 02 5 2019 27 10085126 3 2019 29 4 2019 29 4 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).In cases showing organizing pneumonia (OP) with radiologic findings and pathological images, it is necessary to differentiate between idiopathic and secondary diseases as the cause of OP. Cryptococcus infection as a cause of OP is not well known. We herein report two cases of secondary pulmonary cryptococcosis in immunocompromised patients who showed OP, and the usefulness of bronchoscopy and serum cryptococcal antigen test for an early diagnosis. Common to both cases was that antibiotic therapy and corticosteroid therapy were ineffective, while antifungal agents were effective. In cases of immunocompromised patients who present OP with radiologic findings or pathological images, prompt administration of antifungal treatment at an early stage is important when pulmonary cryptococcosis is identified by bronchoscopy and serum cryptococcal antigen test.\n\nKeywords\nCryptococcosisOrganizing pneumoniaImmunocompromised hostBronchoscopySerum cryptococcal antigen test\n==== Body\nAbbreviations\nBALFbronchoscopy and bronchoalveolar lavage fluid\n\nCTcomputed tomography\n\nIgimmunoglobulin\n\nMTXmethotrexate\n\nOPorganizing pneumonia\n\nPaO2partial pressure of oxygen in arterial blood\n\nPSLprednisolone\n\nTBLBtransbronchial lung biopsy\n\n1 Introduction\nPulmonary cryptococcosis is a fungal infection caused by Cryptococcus neoformans, which is found in the soil and grows in the feces of birds such as pigeons [1]. When the diagnosis and treatment are delayed, it can follow a fatal course by infecting the central nerve system [1]. Pulmonary cryptococcosis is classified as primary cryptococcosis that develops in immunocompetent patients and secondary cryptococcosis that develops in immunocompromised patients. Although the most common radiologic finding is nodular shadows in immunocompetent patients, in immunocompromised patients, the signs of cryptococcosis can easily be confused by the various radiologic findings such as infiltrative shadows besides the nodular shadows [[2], [3], [4], [5]], which may delay timely diagnosis and treatment.\n\nCryptococcus infection as a cause of OP is not well known. Only a few cases have been reported so far [[6], [7], [8], [9], [10]]. We herein report two cases of pulmonary cryptococcosis in immunocompromised patients who showed OP with radiologic findings and pathological images and became worse when receiving corticosteroid therapy. Bronchoscopy and serum cryptococcal antigen test were useful for the diagnosis and prompt administration of antifungal treatment was effective.\n\n2 Case report\n2.1 Patient 1\nA 65-year-old woman was diagnosed as a neurosarcoidosis and oral administration of prednisolone (PSL) 45 mg/day was started. Methotrexate (MTX) 8 mg/week was added 4 months after PSL administration. A month later, she complained of fever and productive cough. A chest computed tomography (CT) revealed an abnormal shadow in the right upper lobe of the lung and right pleural effusion. She was treated with oral levofloxacin, but her symptoms and abnormal chest shadow did not improve. She was referred to our hospital for further examination and treatment.\n\nVital signs were stable and no abnormality was noted in physical examination. Laboratory testing revealed a white blood cell count of 6,670 per mm3, erythrocyte sedimentation rate of 30mm/1h, C-reactive protein of 1.2mg/dl, immunoglobulin (Ig) G of 622 mg/dl. β-D glucan and KL-6 were within normal limits. Chest radiograph showed infiltrative shadows in the upper right lobe and right pleural effusion. Chest CT revealed right dominant non-segmental infiltrative shadows, multiple nodules, and right pleural effusion (Fig. 1a). Although we suspected the possibility of MTX-induced interstitial lung disease and discontinued this treatment, her symptoms and chest radiograph became worse.Fig. 1 (a) Chest CT revealed right dominant non-segmental infiltrative shadows, multiple nodules, and right pleural effusion. (b) Hematoxylin and eosin staining, detecting some of the alveolar spaces containing Masson bodies (circles) and showing high fibrin precipitation and bleeding (arrows). (c) Grocott's silver staining showing the spherical fungi of different sizes. (d) Treatment course of patient 1.\n\nFig. 1\n\nConsidering the immunocompromised host and radiological OP pattern such as non-segmental infiltrative shadows, we had to differentiate between idiopathic, collagen diseases, infection, malignant tumors, and drug reaction as causes of OP, and therefore performed a bronchoscopy obtaining a transbronchial lung biopsy (TBLB) of the right S2 region. The biopsy specimens revealed diffuse lymphocytes in the alveolar wall, and some of the alveolar spaces contained Masson bodies, which was consistent with OP. Moreover, intra-alveolar granulomas and high fibrin precipitation and bleeding, which strongly indicated various degrees of inflammation, were revealed (Fig. 1b). Spherical fungi of large variation sizes of about several μm to 20 μm were revealed by Grocott's silver stain (Fig. 1c). According to the finding of Grocott's silver stain, we considered the possibility of Cryptococcus neoformans or Pneumocystis jirovecii. Mucicarmine staining, which stains the yeast capsule of Cryptococcus red [11], was negative. However, the tissue specimens also lacked the characteristic of Pneumocystis jirovecii such as size uniformity of 4–10 μm, crescent-shaped, helmet-shaped, and intracystic dots. In the culture test of bronchial wash, general bacteria, acid-fast bacteria and fungi were all negative. Furthermore, the serum cryptococcal antigen was positive. It is known that there is the capsule-deficient form of cryptococcus, which is negative of mucicarmine staining [12]. Finally, we diagnosed her as secondary pulmonary cryptococcosis. After fluconazole treatment, her symptoms, chest radiograph and CT finding improved (Fig. 1d).\n\n2.2 Patient 2\nA 76-year-old man was diagnosed with rheumatoid arthritis, and oral administration of PSL 8 mg/day, MTX 4 mg/week and anti-TNF-α monoclonal antibody was therefore started. 5 months after the initiation of treatment, he became feverish. A chest CT revealed infiltrative shadows of the bilateral lung fields and he was hospitalized. At the time of admission, he complained of productive cough, chest pain at inspiration and bloody sputum. MTX and anti-TNF-α monoclonal antibody were discontinued and he was treated with intravenous antibiotics. Even after that, the infiltrative shadows expanded and he developed hypoxemia. Since he did not respond to steroid pulse therapy, he was referred to our hospital.\n\nHis occupation was as a member of the zoo staff, and he had kept birds in the past. Fine crackles were heard over the bilateral lower chest. Chest radiograph showed a decrease in permeability of the bilateral lower lungs and a decrease in the volume of the right lung. Chest CT revealed non-segmental infiltrative shadows with air bronchogram and surrounding ground-glass opacity in the bilateral lungs (Fig. 2a). In the arterial blood gas analysis, partial pressure of oxygen in arterial blood (PaO₂) was 69.6 mmHg. Laboratory testing revealed a white blood cell count of 15,850 per mm³, C-reactive protein of 10.8 mg/dl, IgG of 791 mg/dl. β-D glucan and serum tumor markers in lung cancer was within normal limits. Interferon gamma release assays by T-SPOT were also negative.Fig. 2 (a) Chest CT revealed non-segmental infiltrative shadows with air bronchogram and surrounding ground-glass opacity in bilateral lungs. (b) A few spores of cryptococcus yeast were detected in the smear of BALF by Grocott's silver stain. (c) Treatment course of patient 2.\n\nFig. 2\n\nConsidering an immunocompromised host and radiological OP pattern, infection, malignant tumors, and drug-induced pneumonitis could be cited as a differential diagnosis. He underwent a bronchoscopy and bronchoalveolar lavage fluid (BALF) study performed from left B5 demonstrated a cell population of 76.0% lymphocytes, 10.5% neutrophils, and 4.0% alveolar macrophages. Biopsy could not be performed because he had taken antiplatelet medicine. A few yeast-like fungi were observed by the Grocott's silver stain of BALF. A small number of Cryptococcus neoformans was detected from the fungal culture of BALF (Fig. 2b). The serum cryptococcal antigen was positive, therefore we diagnosed him as secondary pulmonary cryptococcosis. There was no finding suggesting cryptococcal meningitis in cerebrospinal fluid examination. After antifungal treatment, his hypoxemia, chest radiograph and CT finding were improved (Fig. 2c).\n\n3 Discussion\nWe found 2 clinical issues. Secondary cryptococcosis that develops in immunocompromised patients can present as OP with radiologic findings and pathological images, and bronchoscopy and serum cryptococcal antigen test were useful for the differential diagnosis of OP. It was revealed that, in cases of OP during the acute phase of fungal infection, steroid therapy is harmful and treatment for the original disease by antifungal drug should be given priority.\n\nSecondary cryptococcosis can present as OP with radiologic findings and pathological images. In our 2 cases, the radiological OP patterns, such as non-segmental infiltrative shadows, were observed in HRCT. Additionally, in our first case, the pathological OP pattern was proved. Some reports suggested that comparison of HRCT findings be made in primary and secondary cryptococcosis. The most common HRCT finding in primary cryptococcosis was a solitary nodule [[2], [3], [4], [5],7]. On the other hand, secondary cryptococcosis had various radiologic findings such as infiltrative shadows, multiple nodules, and especially the proportion of infiltrative shadows is high [2,7]. For the prevention of infection, the role of cell-medicated immunity centered on Th1 cells is important because Cryptococcus grows in macrophages. When the Th1 immune response is activated, lymphocytes and macrophages surround the Cryptococcus and form granulomas, which are sealed so that the fungus does not diffuse into the surrounding tissues [13,14]. For this reason, the higher proportion of infiltrative shadows may help to explain that containment of Cryptococcus neoformans by lymphocytes and macrophages does not work well in immunocompromised patients.\n\nAlthough OP proved pathologically to be due to Cryptococcus neoformans is not well documented in the literature, it is interesting to note that all cases had infiltrative shadows [[6], [7], [8], [9], [10]]. According to McDonnell's pathological classification of pulmonary cryptococcosis, 4 basic morphologic patterns were observed: peripheral pulmonary granuloma, granulomatous pneumonia, intracapillary/interstitial involvement, and massive pulmonary involvement [15]. Among them, granulomatous pneumonia is typical for immunocompromised patients. In our case, based on the features of intra-alveolar granulomas and surroundings with various degrees of inflammation, it was judged as a granulomatous pneumonia pattern. As discussed so far, if a detailed pathologic examination is performed in secondary cryptococcosis showing infiltrative shadows, pathological OP might have been presented.\n\nBronchoscopy and serum cryptococcal antigen test were useful for the differential diagnosis of OP. Even if pathological OP was obtained, we cannot detect the underlying reason or disease unless detailed examinations are added. Grocott's silver staining is easy to grasp the characteristic structure of fungi and it is indispensable for the identification of fungal species [16]. Furthermore, the positive mucicarmine staining is helpful in distinguishing cryptococci from other fungi. In the serum cryptococcal antigen test, the cutoff value of ≧1:1 showed a sensitivity of 92% and a specificity of 96.5% [17]. For definitive diagnosis, it is necessary to confirm Cryptococcus neoformans by biopsy or fungal culture, but since histopathological diagnosis and culture take time, serum cryptococcal antigen test, which can be carried out simply and quickly, is useful [1].\n\nIn cases showing OP, it is necessary to first consider of immune states because OP is a very specific pattern of lung repair to several different injuries. After that, we have to differentiate between idiopathic, collagen diseases, infection, malignant tumors, and drug-induced as causes of OP [18], because the appropriate treatments differ. If it is caused by idiopathic, collagen diseases or drug-induced, steroid therapy exerts beneficial effects. Conversely, in the case of OP caused by infection such as Cryptococcus neoformans, steroid therapy can worsen the condition [19]. Similarly, our cases were also deteriorated by the steroid therapy. There is an effectiveness of steroids for the OP of post infection. It has been reported that steroid therapy is the best treatment option for OP and the results are good, with up to 80% of individuals cured [20]. However, it has not been known until now whether steroid therapy is effective for OP in the acute phase of infection. Indeed, in the case reports on OP due to cryptococcus infection so far published, treatment with a single steroid had not been tried and so its effect was unknown (Table 1).Table 1 Comparison between past case reports and this case report.\n\nTable 1Case [ref.]\tYear\tAuthor\tAge\nSex\tRadiologic findings\tPathological images\tsCRAG test\tSteroid therapy\tAntifungal therapy\t\n1 [6]\t2004\tKishi et al.\t31\nM\tBilateral consolidations\tOP pattern\t(+)\t(−)\t(+)\t\n2 [7]\t2005\tOuchi et al.\t54\nM\tBilateral infiltrative shadows\tCryptococcus Phagocytosed by Macrophages\t(+)\t(−)\t(+)\t\n3 [8]\t2005\tChantranuwat et al.\t67\nM\tBilateral multiple nodules\tOP pattern, Cryptococcus in alveolar macrophages\tN/A\t(−)\t(+)\t\n4 [9]\t2010\tTaniguchi et al.\t78\nF\tBilateral infiltrative shadows\tMultinucleated giant cell and Cryptococcus\t(+)\t(−)\t(+)\t\n5 [10]\t2010\tKessler et al.\t30\nM\tBilateral consolidations\tOP pattern, multinucleated giant cell with Cryptococcus\t(+)\t(−)\t(+)\t\nPresent case (1)\t2019\t\t65\nF\tBilateral non-segmental infiltrative shadows, multiple nodules\tOP pattern and Cryptococcus\t(+)\t(+)\t(+)\t\nPresent case (2)\t2019\t\t72\nM\tBilateral non-segmental infiltrative shadows\tN/A\t(+)\t(+)\t(+)\t\nRef, reference; sCRAG, serum Cryptococcal Antigen; N/A, not applicable; OP, organizing pneumonia.\n\n\n\nFrom our cases, it was revealed that steroid therapy is harmful if it is OP during fungal infection and that treatment for the original disease by antifungal drugs should be given priority.\n\nIn conclusion, secondary cryptococcosis that develops in immunocompromised patients can present as OP with radiologic findings and pathological images. In cases of immunocompromised patients who present as OP with radiologic findings or pathological images, or in cases in which antibiotics and steroid therapy are not successful, it is useful for the prompt administration of antifungal treatment to differentiate cryptococcal infection and to perform bronchoscopy and serum cryptococcal antigen test from an early stage. Further reports should be accumulated to establish the mechanisms in the pathogenesis of cryptococcosis as a cause of OP.\n\nDeclarations of interest\nNone.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAcknowledgements\nThe authors thank Mr. Brent Bell for reading the manuscript.\n==== Refs\nReferences\n1 Maziarz E.K. Perfect J.R. Cryptococcosis Infect. Dis. Clin. N. Am. 30 1 2016 179 206 E.K. Maziarz, J.R. Perfect, Cryptococcosis, Infect Dis Clin North Am 30(1) (2016) 179-206.\n2 Ogata K. Wataya H. Morooka M. Hamatake M. Kaneko S. Nakahashi H. Hara N. Pulmonary cryptococcosis : two new cases and a comparative historical review of the literature Jpn. Soc. Bronchol. 19 2 1997 122 126 K. Ogata, H. Wataya, M. Morooka, M. Hamatake, S. Kaneko, H. Nakahashi, N. Hara, Pulmonary Cryptococcosis : Two New Cases and a Comparative Historical Review of the Literature, Japan Society for Bronchology 19(2) (1997) 122-126.\n3 Lindell R.M. Hartman T.E. Nadrous H.F. Ryu J.H. Pulmonary cryptococcosis: CT findings in immunocompetent patients Radiology 236 1 2005 326 331 15987984 R.M. Lindell, T.E. Hartman, H.F. Nadrous, J.H. Ryu, Pulmonary cryptococcosis: CT findings in immunocompetent patients, Radiology 236(1) (2005) 326-331.\n4 Kishi K. Homma S. Kurosaki A. Kohno T. Motoi N. Yoshimura K. Clinical features and high-resolution CT findings of pulmonary cryptococcosis in non-AIDS patients Respir. Med. 100 5 2006 807 812 16239102 K. Kishi, S. Homma, A. Kurosaki, T. Kohno, N. Motoi, K. Yoshimura, Clinical features and high-resolution CT findings of pulmonary cryptococcosis in non-AIDS patients, Respir Med 100(5) (2006) 807-812.\n5 Chang W.C. Tzao C. Hsu H.H. Lee S.C. Huang K.L. Tung H.J. Chen C.Y. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients Chest 129 2 2006 333 340 16478849 W.C. Chang, C. Tzao, H.H. Hsu, S.C. Lee, K.L. Huang, H.J. Tung, C.Y. Chen, Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients, Chest 129(2) (2006) 333-340.\n6 Kishi K. Homma S. Kurosaki A. Nakamura S. Yoshimura K. [Primary pulmonary cryptococcosis exhibiting the radiological characteristics of bronchiolitis obliterans organizing pneumonia] Kansenshogaku Zasshi 78 4 2004 327 330 15176237 K. Kishi, S. Homma, A. Kurosaki, S. Nakamura, K. Yoshimura, [Primary pulmonary cryptococcosis exhibiting the radiological characteristics of bronchiolitis obliterans organizing pneumonia], Kansenshogaku Zasshi 78(4) (2004) 327-330.\n7 Ouchi H. Fujita M. Minami T. Inoshima I. Nakanishi Y. Clinical evaluation of pulmonary cryptococcosis: including a case report of pulmonary cryptoccosis mimicking COP and a review of 17 cases Jpn. J. Chest Dis. 64 2 2005 161 166 H. Ouchi, M. Fujita, T. Minami, I. Inoshima, Y. Nakanishi, Clinical evaluation of pulmonary cryptococcosis: Including a case report of pulmonary cryptoccosis mimicking COP and a review of 17 cases, Japanese Journal of Chest Diseases 64(2) (2005) 161-166.\n8 Chantranuwat C. Sittipunt C. Bronchiolitis obliterans organizing pneumonia caused by capsule-deficient cryptococcosis Southeast Asian J. Trop. Med. Publ. Health 36 1 2005 174 177 C. Chantranuwat, C. Sittipunt, Bronchiolitis obliterans organizing pneumonia caused by capsule-deficient cryptococcosis, Southeast Asian J Trop Med Public Health 36(1) (2005) 174-177.\n9 Taniguci H. Hayashi T. Uchiyama A. Kambara K. Abo H. Shinnou H. Miyazawa H. Noto H. Izumi S. A case of pulmonary cyptococcosis mimicking organizing pneumonia Jpn. J. Chest Dis. 69 12 2010 1144 1147 H. Taniguci, T. Hayashi, A. Uchiyama, K. Kambara, H. Abo, H. Shinnou, H. Miyazawa, H. Noto, S. Izumi, A case of pulmonary cyptococcosis mimicking organizing pneumonia, Japanese Journal of Chest Diseases 69(12) (2010) 1144-1147.\n10 Kessler A.T. Al Kharrat T. Kourtis A.P. Cryptococcus neoformans as a cause of bronchiolitis obliterans organizing pneumonia J. Infect. Chemother. 16 3 2010 206 209 20169387 A.T. Kessler, T. Al Kharrat, A.P. Kourtis, Cryptococcus neoformans as a cause of bronchiolitis obliterans organizing pneumonia, J Infect Chemother 16(3) (2010) 206-209.\n11 Lazcano O. Speights V.O. Jr. Bilbao J. Becker J. Diaz J. Combined Fontana-Masson-mucin staining of cryptococcus neoformans Arch. Pathol. Lab Med. 115 11 1991 1145 1149 1720948 O. Lazcano, V.O. Speights, Jr., J. Bilbao, J. Becker, J. Diaz, Combined Fontana-Masson-mucin staining of Cryptococcus neoformans, Arch Pathol Lab Med 115(11) (1991) 1145-1149.\n12 Harding S.A. Scheld W.M. Feldman P.S. Sande M.A. Pulmonary infection with capsule-deficient cryptococcus neoformans Virchows Arch. A Pathol. Anat. Histol. 382 1 1979 113 118 157594 S.A. Harding, W.M. Scheld, P.S. Feldman, M.A. Sande, Pulmonary infection with capsule-deficient cryptococcus neoformans, Virchows Arch A Pathol Anat Histol 382(1) (1979) 113-118.\n13 Voelz K. May R.C. Cryptococcal interactions with the host immune system Eukaryot. Cell 9 6 2010 835 846 20382758 K. Voelz, R.C. May, Cryptococcal interactions with the host immune system, Eukaryot Cell 9(6) (2010) 835-846.\n14 Sato K. Kawakami K. Recognition of cryptococcus neoformans by pattern recognition receptors and its role in host defense to this infection Med. Mycol. J 58 3 2017 J83 J90 28855484 K. Sato, K. Kawakami, Recognition of Cryptococcus neoformans by Pattern Recognition Receptors and its Role in Host Defense to This Infection, Med Mycol J 58(3) (2017) J83-J90.\n15 McDonnell J.M. Hutchins G.M. Pulmonary cryptococcosis Hum. Pathol. 16 2 1985 121 128 3972394 J.M. McDonnell, G.M. Hutchins, Pulmonary cryptococcosis, Hum Pathol 16(2) (1985) 121-128.\n16 Guarner J. Brandt M.E. Histopathologic diagnosis of fungal infections in the 21st century Clin. Microbiol. Rev. 24 2 2011 247 280 21482725 J. Guarner, M.E. Brandt, Histopathologic diagnosis of fungal infections in the 21st century, Clin Microbiol Rev 24(2) (2011) 247-280.\n17 Tanaka K. Kohno S. Miyazaki T. Miyazaki H. Mitsutake K. Maesaki S. Kaku M. Koga H. The Eiken Latex test for detection of a cryptococcal antigen in cryptococcosis. Comparison with a monoclonal antibody-based latex agglutination test, Pastorex Cryptococcus Mycopathologia 127 3 1994 131 134 7808506 K. Tanaka, S. Kohno, T. Miyazaki, H. Miyazaki, K. Mitsutake, S. Maesaki, M. Kaku, H. Koga, The Eiken Latex test for detection of a cryptococcal antigen in cryptococcosis. Comparison with a monoclonal antibody-based latex agglutination test, Pastorex Cryptococcus, Mycopathologia 127(3) (1994) 131-134.\n18 Epler G.R. Bronchiolitis obliterans organizing pneumonia Arch. Intern. Med. 161 2 2001 158 164 11176728 G.R. Epler, Bronchiolitis obliterans organizing pneumonia, Arch Intern Med 161(2) (2001) 158-164.\n19 Perfect J.R. Dismukes W.E. Dromer F. Goldman D.L. Graybill J.R. Hamill R.J. Harrison T.S. Larsen R.A. Lortholary O. Nguyen M.H. Pappas P.G. Powderly W.G. Singh N. Sobel J.D. Sorrell T.C. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America Clin. Infect. Dis. 50 3 2010 291 322 20047480 J.R. Perfect, W.E. Dismukes, F. Dromer, D.L. Goldman, J.R. Graybill, R.J. Hamill, T.S. Harrison, R.A. Larsen, O. Lortholary, M.H. Nguyen, P.G. Pappas, W.G. Powderly, N. Singh, J.D. Sobel, T.C. Sorrell, Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america, Clin Infect Dis 50(3) (2010) 291-322.\n20 Epler G.R. Bronchiolitis obliterans organizing pneumonia, 25 years: a variety of causes, but what are the treatment options? Expert Rev. Respir. Med. 5 3 2011 353 361 21702658 G.R. Epler, Bronchiolitis obliterans organizing pneumonia, 25 years: a variety of causes, but what are the treatment options?, Expert Rev Respir Med 5(3) (2011) 353-361.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "27()",
"journal": "Respiratory medicine case reports",
"keywords": "Bronchoscopy; Cryptococcosis; Immunocompromised host; Organizing pneumonia; Serum cryptococcal antigen test",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "100851",
"pmc": null,
"pmid": "31110941",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11176728;15176237;157594;15906663;15987984;16239102;16478849;1720948;20047480;20169387;20382758;21482725;21702658;26897067;28855484;3972394;7808506",
"title": "Cryptococcosis as a cause of organizing pneumonia.",
"title_normalized": "cryptococcosis as a cause of organizing pneumonia"
} | [
{
"companynumb": "PHHY2019JP123500",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nAccumulation of ascites fluid is a major obstacle in the late phase of epithelial ovarian cancer. However, there is no consensus on a specific treatment for malignant ascites. The present study evaluated the clinical benefit of half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks).\n\n\nMETHODS\nThis was a single-arm interventional study performed at Aichi Cancer Center Hospital. Four patients with platinum-resistant epithelial ovarian cancer and symptomatic malignant ascites were no longer considered candidates for standard chemotherapy. As a palliative approach, half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks) was used with informed consent. The clinical data of these patients were retrospectively reviewed.\n\n\nRESULTS\nAll patients had been heavily pretreated and showed progressive disease. Thus, standard chemotherapy was no longer feasible, and palliative paracentesis for malignant ascites was clinically needed. Among the four patients, three did not require additional paracentesis after bevacizumab therapy, and there were no adverse events. One patient needed paracentesis owing to lymphorrhea.\n\n\nCONCLUSIONS\nThe use of bevacizumab therapy as a palliative approach for malignant ascites might be an option in patients with terminal-stage ovarian cancer. However, further evaluation is needed with regard to the possibility of severe side effects and medical expenses.",
"affiliations": "Department of Gynecologic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.;Department of Obstetrics and Gynecology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.",
"authors": "Shimizu|Yusuke|Y|;Kajiyama|Hiroaki|H|https://orcid.org/0000-0003-0493-1825;Yoshida|Kosuke|K|https://orcid.org/0000-0003-1484-4872;Tamauchi|Satoshi|S|https://orcid.org/0000-0003-3130-3736;Nakanishi|Toru|T|;Kikkawa|Fumitaka|F|https://orcid.org/0000-0002-7170-780X",
"chemical_list": "D000068258:Bevacizumab",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "45(12)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "bevacizumab; malignant ascites; ovarian carcinoma; palliative care",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000368:Aged; D001201:Ascites; D000068258:Bevacizumab; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "2435-2439",
"pmc": null,
"pmid": "31468618",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The usefulness of bevacizumab for relief from symptomatic malignant ascites in patients with heavily treated recurrent ovarian cancer.",
"title_normalized": "the usefulness of bevacizumab for relief from symptomatic malignant ascites in patients with heavily treated recurrent ovarian cancer"
} | [
{
"companynumb": "JP-ACCORD-168732",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Intrauterine devices (IUDs) are highly effective at preventing pregnancy. Levonorgestrel (LNG) IUDs also have beneficial effects on menstrual bleeding and abdominal and pelvic pain. Although there are increasing data on use of IUDs for contraception in adolescents and for medical indications in adults, there are extremely limited data on LNG IUD use for medical indications in adolescents. Our objective is to describe the characteristics and experiences of LNG IUD use in nulliparous adolescents and young women using IUDs for medical indications.\n\n\n\nWe conducted a retrospective chart review of all nulliparous patients aged 22 years and younger who underwent LNG IUD insertion at a tertiary care children's hospital between July 1, 2004 and June 30, 2014 primarily for noncontraceptive indications. Descriptive statistical analysis was performed.\n\n\n\nWe identified 231 LNG IUDs placed in 219 nulliparous women for medical indications during this time period. Mean patient age was 16.8 years (±2.2). Only 41% reported ever being sexually active. IUD continuation rate at 1 year was 86%. The amenorrhea rate at 1 year was 51%. Approximately 80% of women reported improvements in menstrual bleeding and abdominal and pelvic pain. Side effects and complications were low.\n\n\n\nThis study provides evidence that LNG IUDs are effective, well-tolerated, and safe menstrual management options in young nulliparous women, including younger adolescents and those who have never been sexually active. This method is an excellent first-line therapy option for adolescents and young women for both contraceptive and noncontraceptive indications, regardless of age, parity, or sexual activity.",
"affiliations": "Division of Pediatric and Adolescent Gynecology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Obstetrics and Gynecology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: beth.schwartz@jefferson.edu.;Division of Pediatric and Adolescent Gynecology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Pediatric and Adolescent Gynecology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio.",
"authors": "Schwartz|Beth I|BI|;Alexander|Morgan|M|;Breech|Lesley L|LL|",
"chemical_list": "D003271:Contraceptive Agents, Female; D016912:Levonorgestrel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jadohealth.2020.05.041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-139X",
"issue": "68(2)",
"journal": "The Journal of adolescent health : official publication of the Society for Adolescent Medicine",
"keywords": "Abnormal uterine bleeding; Adolescent; Dysmenorrhea; Endometriosis; Heavy menstrual bleeding; Intrauterine device; Never sexually active; Nulliparous",
"medline_ta": "J Adolesc Health",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003271:Contraceptive Agents, Female; D005260:Female; D006801:Humans; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D008598:Menstruation; D010298:Parity; D011247:Pregnancy; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9102136",
"other_id": null,
"pages": "357-363",
"pmc": null,
"pmid": "32646831",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Levonorgestrel Intrauterine Device Use for Medical Indications in Nulliparous Adolescents and Young Adults.",
"title_normalized": "levonorgestrel intrauterine device use for medical indications in nulliparous adolescents and young adults"
} | [
{
"companynumb": "US-BAYER-2020-151402",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "This report describes the review and update of a set of minimum recommendations for the toxicological investigation of suspected alcohol and drug-impaired driving cases and motor vehicle fatalities involving drugs or alcohol. The recommendations have the goal of ensuring that a consistent set of data regarding the most frequently encountered drugs linked to driving impairment is collected for practical application in the investigation of these cases and to allow epidemiological monitoring and the development of evidence-based public policy on this important public safety issue. The recommendations are based on a survey of practices in US laboratories performing this kind of analysis, consideration of existing epidemiological crash and arrest data and practical considerations of widely available technology platforms in laboratories performing this work. The final recommendations were derived from a consensus meeting of experts recruited from survey respondents and the membership of the National Safety Council's Alcohol, Drug and Impairment Division (formerly known as the Committee on Alcohol and Other Drugs, CAOD).",
"affiliations": "1Center for Forensic Science Research and Education, Fredric Rieders Family Renaissance Foundation, Willow Grove, PA, USA.",
"authors": "Logan|Barry K|BK|;Lowrie|Kayla J|KJ|;Turri|Jennifer L|JL|;Yeakel|Jillian K|JK|;Limoges|Jennifer F|JF|;Miles|Amy K|AK|;Scarneo|Colleen E|CE|;Kerrigan|Sarah|S|;Farrell|Laurel J|LJ|",
"chemical_list": "D013287:Illicit Drugs",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkt059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "37(8)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000063:Accidents, Traffic; D001334:Automobile Driving; D053593:Forensic Toxicology; D017408:Guidelines as Topic; D006801:Humans; D013287:Illicit Drugs; D012463:Saliva; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "552-8",
"pmc": null,
"pmid": "23943437",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recommendations for toxicological investigation of drug-impaired driving and motor vehicle fatalities.",
"title_normalized": "recommendations for toxicological investigation of drug impaired driving and motor vehicle fatalities"
} | [
{
"companynumb": "US-JNJFOC-20140303523",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nChromosomal ploidy is a major risk stratification tool for acute B-cell lymphoblastic leukemia (B-ALL). Low hypodiploidy and near-haploidy are thought to be confined to pediatric B-ALL and associated with a poor prognosis. Doubling of either a low-hypodiploid or a near-haploid clone results in an apparently high-hyperdiploid karyotype, which is often misclassified for risk.\n\n\nMETHODS\nWe studied four patients with B-ALL who had chromosome genomic array testing (CGAT), along with fluorescence in situ hybridization and mutation testing.\n\n\nRESULTS\nWe identified a unique case of adult B-ALL with masked low hypodiploidy (mLH) by genomic duplication, along with a somatic deletion of the IKZF3 gene and a somatic TP53 mutation. Three cases of pediatric B-ALL with mLH, two with TP53 mutations and one untested, were also identified and compared with the adult patient.\n\n\nCONCLUSIONS\nCGAT was critical in the genotype clarification of these cases through detection of copy-neutral loss of heterozygosity and should be considered performing for B-ALL with apparent hyperdiploidy for accurate prognostic risk stratification and treatment planning.",
"affiliations": "From the Fred Hutchinson Cancer Research Center, Seattle, WA; University of Washington, Seattle; Seattle Cancer Care Alliance, Seattle, WA; mfang@fhcrc.org.;From the Fred Hutchinson Cancer Research Center, Seattle, WA; University of Washington, Seattle;;From the Fred Hutchinson Cancer Research Center, Seattle, WA; University of Washington, Seattle;;From the Fred Hutchinson Cancer Research Center, Seattle, WA; University of Washington, Seattle; Seattle Cancer Care Alliance, Seattle, WA;;From the Fred Hutchinson Cancer Research Center, Seattle, WA; University of Washington, Seattle; Seattle Cancer Care Alliance, Seattle, WA;;Texas Children's Cancer and Hematology Centers and Department of Pediatrics, Baylor College of Medicine, Houston;;Texas Children's Cancer and Hematology Centers and Department of Pediatrics, Baylor College of Medicine, Houston;;Texas Children's Cancer and Hematology Centers and Department of Pediatrics, Baylor College of Medicine, Houston;;Texas Children's Cancer and Hematology Centers and Department of Pediatrics, Baylor College of Medicine, Houston;;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; and.;Texas Children's Cancer and Hematology Centers and Department of Pediatrics, Baylor College of Medicine, Houston;;Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Fang|Min|M|;Becker|Pamela S|PS|;Linenberger|Michael|M|;Eaton|Keith D|KD|;Appelbaum|Frederick R|FR|;Dreyer|ZoAnn|Z|;Airewele|Gladstone|G|;Redell|Michele|M|;Lopez-Terrada|Dolores|D|;Patel|Ankita|A|;Rabin|Karen R|KR|;Lu|Xinyan|X|",
"chemical_list": "C106285:IKZF3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051740:Ikaros Transcription Factor",
"country": "England",
"delete": false,
"doi": "10.1309/AJCPW83OXPYKPEEN",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "144(2)",
"journal": "American journal of clinical pathology",
"keywords": "B-cell lymphoblastic leukemia; IKZF; TP53; chromosome genomic array testing; copy-neutral loss of heterozygosity; single-nucleotide polymorphism array",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D051740:Ikaros Transcription Factor; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53; D055815:Young Adult",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "263-70",
"pmc": null,
"pmid": "26185311",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adult Low-Hypodiploid Acute B-Lymphoblastic Leukemia With IKZF3 Deletion and TP53 Mutation: Comparison With Pediatric Patients.",
"title_normalized": "adult low hypodiploid acute b lymphoblastic leukemia with ikzf3 deletion and tp53 mutation comparison with pediatric patients"
} | [
{
"companynumb": "US-BAXTER-2015BAX067305",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "The objective of the present study was to assess the safety and tolerability of cefazolin therapy among patients with methicillin-sensitive Gram-positive bacterial infections who develop non-IgE-mediated hypersensitivity reactions (HSRs) to nafcillin. In this retrospective cohort analysis of the Outpatient Parenteral Antimicrobial Therapy program at the Massachusetts General Hospital from 2007 through 2013, we identified patients switched from nafcillin to cefazolin after an immune-mediated HSR. We reviewed patient demographics, details about the original HSR, and outcomes after the switch to cefazolin therapy. HSRs were classified by reaction type and likely mechanism. There were 467 patients treated with nafcillin, of which 60 (12.8%) were switched to cefazolin during their prescribed course. Of the 60 patients who transitioned to cefazolin, 17 (28.3%) were switched because of non-IgE-mediated HSRs. HSRs included maculopapular rash (n = 10), immune-mediated nephritis (n = 3), isolated eosinophilia (n = 2), immune-mediated hepatitis (n = 1), and a serum sickness-like reaction (n = 1). All but one patient (94.1%) who switched to cefazolin tolerated the drug with resolution of the HSR and completed their therapy with cefazolin. No patient experienced worsening of their rash or progressive organ dysfunction. With appropriate monitoring, therapy with cefazolin after non-IgE-mediated HSRs to nafcillin appears to be safe.",
"affiliations": "Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA Harvard Medical School, Boston Massachusetts, USA kblumenthal1@partners.org.;Harvard Medical School, Boston Massachusetts, USA Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.;Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA Harvard Medical School, Boston Massachusetts, USA Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Infection Control Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Harvard Medical School, Boston Massachusetts, USA.;Harvard Medical School, Boston Massachusetts, USA Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.",
"authors": "Blumenthal|Kimberly G|KG|;Youngster|Ilan|I|;Shenoy|Erica S|ES|;Banerji|Aleena|A|;Nelson|Sandra B|SB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007155:Immunologic Factors; D009254:Nafcillin; D002437:Cefazolin; D008712:Methicillin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02504-13",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "58(6)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002437:Cefazolin; D015331:Cohort Studies; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008712:Methicillin; D008875:Middle Aged; D009254:Nafcillin; D010045:Outpatients; D012189:Retrospective Studies",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "3137-43",
"pmc": null,
"pmid": "24637693",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "20211890;10329829;19563995;21702250;20934625;22904350;14530782;10359904;23009177;23030831;3890535;22011388;16004164;8957644;17653125;17349459;9069593;24275265;15985813;15561842;16466894;22445493;10524959;7759811;4791486;21217178;4744022;21710108;15461594;10507273;17173215;20731577;22844299;16451776;2977302;9636842;22644982;19483522;9402411;14671029;15227610;19487449;15529116;18653431;23964554;9161625;4176988;19767623;11731945;17493182;21371655;8565754;23873883;15805383;24565482;24107387;8237951;21162721;18164908;19106348",
"title": "Tolerability of cefazolin after immune-mediated hypersensitivity reactions to nafcillin in the outpatient setting.",
"title_normalized": "tolerability of cefazolin after immune mediated hypersensitivity reactions to nafcillin in the outpatient setting"
} | [
{
"companynumb": "PHHY2014US142462",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NAFCILLIN\\NAFCILLIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "Due to the emergence of Staphylococcus aureus with reduced vancomycin susceptibility, newer antibiotics, including daptomycin, have been used to treat methicillin-resistant S aureus infections. Daptomycin is a cyclic lipopeptide that is approved to treat S aureus bacteremia and right-sided endocarditis, and reports of S aureus with reduced susceptibility to daptomycin are infrequent. To our knowledge, the present report describes the first Canadian case of daptomycin-nonsusceptible, vancomycin-intermediate S aureus infection.",
"affiliations": "Michael G DeGroote School of Medicine, McMaster University;",
"authors": "Yu|Ryan|R|;Dale|Suzanne E|SE|;Yamamura|Deborah|D|;Stankus|Vida|V|;Lee|Christine|C|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2012/138470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1712-9532",
"issue": "23(2)",
"journal": "The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale",
"keywords": "Daptomycin nonsusceptible; Endocarditis; Methicillin-resistant Staphylococcus aureus; Vancomycin intermediate resistance",
"medline_ta": "Can J Infect Dis Med Microbiol",
"mesh_terms": null,
"nlm_unique_id": "101226876",
"other_id": null,
"pages": "e48-50",
"pmc": null,
"pmid": "23730321",
"pubdate": "2012",
"publication_types": "D002363:Case Reports",
"references": "20065327;10952568;16323115;18199793;16495273;17954690;11266410;16207998;19233622;16207957;19436507;19106348;16436693;11574559;21629617;18790610;16847029;17620372;18838599;15980337;14727222;11871491;21208910",
"title": "Daptomycin-nonsusceptible, vancomycin-intermediate, methicillin-resistant Staphylococcus aureus endocarditis.",
"title_normalized": "daptomycin nonsusceptible vancomycin intermediate methicillin resistant staphylococcus aureus endocarditis"
} | [
{
"companynumb": "CA-MYLANLABS-2017M1051365",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.\n\n\n\nAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.\n\n\n\nOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27-160), and 28 days from start of immunotherapy (IQR 9-71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis.\n\n\n\nEpilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.",
"affiliations": "From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.;From the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands. m.titulaer@erasmusmc.nl.",
"authors": "de Bruijn|Marienke A A M|MAAM|;van Sonderen|Agnes|A|;van Coevorden-Hameete|Marleen H|MH|;Bastiaansen|Anna E M|AEM|;Schreurs|Marco W J|MWJ|;Rouhl|Rob P W|RPW|;van Donselaar|Cees A|CA|;Majoie|Marian H J M|MHJM|;Neuteboom|Rinze F|RF|0000-0001-6136-4981;Sillevis Smitt|Peter A E|PAE|;Thijs|Roland D|RD|;Titulaer|Maarten J|MJ|",
"chemical_list": "D000927:Anticonvulsants; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D018079:Receptors, GABA",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000007475",
"fulltext": "\n==== Front\nNeurology\nNeurology\nneurology\nneur\nneurology\nNEUROLOGY\nNeurology\n0028-3878\n1526-632X\nLippincott Williams & Wilkins Hagerstown, MD\n\n30979857\nNEUROLOGY2018934414\n10.1212/WNL.0000000000007475\n60\n61\n132\nArticle\nEvaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis\nde Bruijn Marienke A.A.M. MD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nvan Sonderen Agnes MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nvan Coevorden-Hameete Marleen H. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nBastiaansen Anna E.M. MD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nSchreurs Marco W.J. PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\n(1) Thermo Scientific, funding for travel to conference (2) Inova, funding for travel to conference\n\nEditorial Boards:\n\n(1) Nederlands tijdschrift voor Allergie & Astma, editorial advisory board member, 2015-\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\n(1) Combined ophthalmic research, Rotterdam (2) Stichting de Merel, Den Haag (3) Stichting Blindenbelangen, Rotterdam\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nRouhl Rob P.W. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\n1) UCB Pharma, compensation for lectures\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\n1) FHML Scannexus Fund 2) Center for Integrative Neurosciences Fund\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nvan Donselaar Cees A. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nMajoie Marian H.J.M. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nErasmus + Projectnumber: 20 18- 1-NL0 1-KA203-O39O7O Projecttitle: European Partnership on Competencies for High Value COst COnscious CARE.\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nhttp://orcid.org/0000-0001-6136-4981\nNeuteboom Rinze F. MD, PhD Scientific Advisory Boards:\n\nData safety monitory board: EXCEL study (neurofibromatosis) (non profit entity()\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nSillevis Smitt Peter A.E. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nP. Sillevis Smitt holds a patent for the detection of anti- DNER.\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nPeter Sillevis Smitt received a research grant from Euroimmun.\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nThijs Roland D. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\nMedtronic: speakers and travel honorarium UCB: speakers honorarium GSK: speakers honorarium\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\n(1) Medtronic Inc.\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nDutch Epilepsy Foundation Nuts Ohra Foundation AC Thomson Foundation The Netherlands Organisation for Health Research and Development (ZonMW)\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nTitulaer Maarten J. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\n(1) Neurology: Neuroimmunology & Neuroinflammation, since June 2014\n\nPatents:\n\n(1) filed a patent for\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\n(1) Medimmune LLC, research funds for serving on the scientific advisory board; (2) Guidepoint Global LLC, research funds for consultancy; (3) Novartis, research funds for teaching; (4) unrestricted research grant from Euroimmun AG.\n\nResearch Support, Government Entities:\n\n(1) supported by the Netherlands Organisation for Scientific Research (NWO, Veni incentive and Memorabel initiative)\n\nResearch Support, Academic Entities:\n\n(1) Previously supported by an ErasmusMC fellowship\n\nResearch Support, Foundations and Societies:\n\n(1) supported by the Dutch Epilepsy Foundations, projectnumber 14-19.\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nFrom the Departments of Neurology (M.A.A.M.d.B., A.v.S., M.H.v.C.-H., A.E.M.B., P.A.E.S.S., M.J.T.), Immunology (M.W.J.S.), and Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), the Hague; Department of Neurology (R.P.W.R., M.H.J.M.M.), Maastricht UMC+, Maastricht; Department of Neurology (C.A.v.D.), Maasstad Hospital, Rotterdam; Department of Neurology (M.J.M.M.), Academic Center of Epileptology Kempenhaeghe; Sophia Children's Hospital (R.F.N.), Rotterdam; Department of Neurology (R.D.T.), Stichting Epilepsie Instellingen Nedederland (SEIN), Heemstede; and Department of Neurology (R.D.T.), Leiden University Medical Center (LUMC), the Netherlands.\nCorrespondence Dr. Titulaer m.titulaer@erasmusmc.nl\nGo to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.\n\nThe Article Processing Charge was funded by Erasmus University.\n\n07 5 2019\n07 5 2019\n92 19 e2185e2196\n18 9 2018\n10 1 2019\nCopyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2019\nAmerican Academy of Neurology\nThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nObjective\n\nThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.\n\nMethods\n\nAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.\n\nResults\n\nOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27–160), and 28 days from start of immunotherapy (IQR 9–71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis.\n\nConclusion\n\nEpilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.\n\nOPEN-ACCESSTRUE\nSTATUSONLINE-ONLY\n==== Body\nThe discovery of NMDA receptor (NMDAR) antibodies1 has led to the description of several other antibodies to extracellular neuronal antigens. Binding of these antibodies leads to cerebral dysfunction, which often manifests as limbic encephalitis characterized by cognitive decline, behavioral changes, and seizures. Seizures occur most frequently in autoimmune encephalitis (AIE) with leucine-rich glioma-inactivated 1 (LGI1),2 NMDAR antibodies,3 and gamma-aminobutyric-acid B receptor (GABABR) antibodies.4\n\nThe description of seizures in AIE has led to a new field of interest in epileptology with challenging issues in diagnosis and treatment. Concerning diagnosis, patients can present with seizures without other notable encephalitis signs,5–7 leading to diagnostic difficulties and treatment delay. Treatment delay is associated with a poorer outcome.3 Therefore, it is essential to consider an autoimmune etiology in presence of specific clinical clues. Moreover, faciobrachial dystonic seizures (FBDS)2 are considered pathognomonic for anti-LGI1 encephalitis. Alternatively, the subacute onset of drug-resistant seizures might be a common, but indiscriminative, feature.\n\nAnother challenging issue is to achieve seizure freedom rapidly. Seizures often seem unresponsive to antiepileptic drugs (AEDs), while responses to immunotherapy are considered good. Nevertheless, seizure freedom is not always achieved while using immunotherapy alone and AEDs are sometimes needed as well.\n\nThe overall efficacy of AEDs in these patients and whether any particular AEDs should be preferred is unclear. Therefore, the aim of this nationwide observational cohort study was to evaluate the responses to AEDs and immunotherapy in these syndromes, including safety, and to describe the risk for epilepsy after resolved encephalitis.\n\nMethods\n\nPatients\n\nThe department of neurology of the Erasmus MC University Medical Center is the national referral site for patients with suspected AIE and the department of immunology is the national referral site for antineuronal antibody testing. We identified all Dutch adults and children with AIE with LGI1, NMDAR, or GABABR antibodies. Patients were identified between August 1999 and May 2017, although 78% were identified after 2010. Antibodies were detected in serum or in CSF and confirmed with both cell-based assay and immunohistochemistry.8 Patients with new-onset seizures during their active disease course were included.\n\nStandard protocol approvals, registrations, and patient consents\n\nThe medical ethics committee of the Erasmus MC University Medical Center approved this study. Written informed consent was obtained from all patients.\n\nSeizures\n\nMedical information about disease course, seizure type, status epilepticus, types of AEDs and immunotherapies used, and side effects of the different treatments were collected during a visit to our clinic (n = 77), from interviews with patients and relatives by phone (n = 27), and from medical files (n = 49). Clinical characteristics, including all encephalitis signs, of a part of the patients have been published before.9,10 To provide an overview of the clinical signs, we allocated patients into 2 groups: epileptic seizures plus and encephalitis. No patients had only epileptic seizures without any other neurologic symptoms at thorough examination. Epileptic seizures plus contained the patients with prominent seizures and only subtle other encephalitis signs, which were initially unrecognized or considered side effects of AEDs. Examples are mild cognitive complaints, behavioral disorders, or subtle movement disorders. Limbic encephalitis was defined as an encephalitis with predominant clinical involvement of the limbic system (short-term memory loss, difficulty forming new memories, behavioral disorder) or MRI fluid-attenuated inversion recovery/T2 abnormalities in the medial temporal lobes.11\n\nThe guidelines and new epilepsy classification of the International League Against Epilepsy (ILAE) were used to define epileptic seizures,12 epileptic seizures with an immune etiology,13 status epilepticus,14 and drug-resistant epileptic seizures,15 and to classify seizures.12,13,16 Epileptic seizures with an immune etiology were defined as at least 2 seizures, not provoked by other factors, occurring more than 24 hours apart resulting directly from an immune disorder, and with evidence of autoimmune-mediated CNS inflammation.12,16 Drug-resistant epileptic seizures were defined as failure to achieve seizure freedom, despite treatment with 2 tolerated, adequately dosed AEDs. Seizures were classified as focal or tonic–clonic. Moreover, focal seizures were classified as seizures with or without impaired awareness. FBDS were defined as frequent attacks (>8/d) with a dystonic posture of the arm, often combined with a facial contraction, lasting less than 30 seconds.2 Refractory status epilepticus was defined as status epilepticus continuing even after adequate treatment. Seizure freedom was defined as no clinical signs of seizures, meaning no seizures observed and no reporting of focal seizures (including auras) or tonic-clonic seizures by patients or physicians. At follow-up, seizures needed to be absent for at least 3 months.\n\nEffectivity of AEDs was scored as ineffective, some effect, seizure freedom, or unknown effect. As this was no formal prospective study, some effects were difficult to assess precisely, and we could therefore not use frequently used variables like 50% seizure reduction. We only scored some effect when it was noted specifically as a considerable reduction. Level of functioning was measured with the modified Rankin Scale (mRS).17\n\nPrimary outcome measures were (1) seizure freedom achieved while using AEDs and while using immunotherapy, (2) days to seizure freedom from start of AEDs and from start of immunotherapy, (3) development of epilepsy after resolved encephalitis, and (4) reported side effects.\n\nStatistics\n\nComparisons between 2 groups were performed with the Mann-Whitney U test (days to seizure freedom after start of epileptic seizures). Comparisons between multiple groups were performed with the Kruskal-Wallis test (age at onset, days to seizures after disease onset), the Fisher-Freeman-Halton test (comparing effects of different AEDs), and the one-way analysis of variance (sex, seizures presenting symptom, type of seizures at presentation and during disease course, and [refractory] status epilepticus).\n\nThe chances to achieve seizure freedom (during first disease episode) were compared by McNemar test, only in patients using both AED and immunotherapy before seizure freedom to avoid confounding by indication. For each patient individually, achievement of seizure freedom after the different treatments is shown visually in the figures. McNemar test was also used to compare AED treatment responses in patients receiving multiple AEDs. The Wilcoxon signed rank test was used to compare the days to seizure freedom from start of AEDs and from start of immunotherapy. For this test only responses of patients who were treated with both AEDs and immunotherapy before seizure freedom were evaluated.\n\np Values below 0.05 were considered significant. We used SPSS 21.0 (SPSS Inc., Chicago, IL) for Windows and Prism7 (GraphPad Software, La Jolla, CA) for Windows for statistical analysis.\n\nData availability statement\n\nAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared upon request from any qualified investigator, maintaining anonymization of the individual patients.\n\nResults\n\nPatient and seizure characteristics\n\nWe identified 153 patients with AIE, including 53 patients with LGI1 antibodies, 75 patients with NMDAR antibodies, and 25 patients with GABABR antibodies. Among these cases, 72% of patients (n = 110) had epileptic seizures with an immune origin (87% LGI1, 57% NMDAR, 84% GABABR), while 14 additional patients (9%) had only one seizure. Table 1 shows seizure characteristics per antibody. Patients with NMDAR antibodies were younger (p < 0.0001) and only in this group there was a female predominance (p < 0.0001). Fourteen patients were categorized as having epileptic seizures plus (10/46 [22%] with LGI1 antibodies, 4/43 [9%] with NMDAR antibodies, and 0/21 with GABABR antibodies); the others had limbic encephalitis or panencephalitis.\n\nTable 1 Patient and seizure characteristics\n\nFBDS only occurred in patients with LGI1 antibodies (53%). All patients with GABABR antibodies had tonic-clonic seizures, compared to 55% of patients with LGI1 antibodies (p = 0.0002), and 79% of patients with NMDAR antibodies. Status epilepticus occurred frequently (n = 38, 34%), in particular in patients with GABABR antibodies (62%, p = 0.006), of whom 26 (68%) had a refractory status epilepticus. Five patients (4%) died during status epilepticus.\n\nMedian follow-up time from onset of seizures was 27 months (interquartile range [IQR] 15–49, range 0–149 months); 24 patients had died (22%). Twenty-five patients (23%) had a relapse of the encephalitis; among them, 76% again had seizures (10 LGI1, 5 NMDAR, 4 GABABR). At last follow-up, 66% of patients had an mRS of 0–2 (LGI1 78%, NMDAR 74%, GABABR 24%).\n\nSeizure treatment\n\nOf all 110 patients with new-onset epileptic seizures with an immune origin, 91% were treated with 1 or more AEDs (LGI1 80%, NMDAR 98%, GABABR 100%). The median delay between seizure onset and start of AEDs was 3 days (IQR 0–31). This delay was higher in patients with anti-LGI1 encephalitis (median 64 days, IQR 0–178, p < 0.0001). During their disease course, patients were treated with a median of 2 AEDs (IQR 1–3, range 0–9). Moreover, 71 patients (65%) were treated with 2 or more AEDs. AEDs were continued for a median period of 8 months after diagnosis (IQR 4–18, range 0–102 months).\n\nMost patients were treated with immunotherapy (92%), all but one with first-line immunotherapy (combination of methylprednisolone or IV immunoglobulins or plasmapheresis), and 17% with additional second-line immunotherapy (rituximab or cyclophosphamide; table 2). The patients not treated with immunotherapy received only AEDs (n = 9). Twenty-one percent of patients were treated with chronic immunotherapy, including azathioprine (n = 15) or mycophenolate (n = 8); of them, 19 (83%) had LGI1 antibodies. Fifteen of 19 anti-LGI1 patients were treated with chronic immunotherapy after the initial episode. Two of these anti-LGI1 patients (13%) developed a relapse, necessitating adaptation of the chronic immunotherapy. Thirty-one anti-LGI1 patients did not receive chronic immunotherapy after the initial episode. Of these, 11 developed a relapse (35%). Four patients had only started chronic immunotherapy after relapse. One of these 4 patients developed multiple relapses that halted after administration of rituximab.\n\nTable 2 Overview of all patients treated with immunotherapy\n\nThe majority of patients with anti-NMDAR and anti-GABABR encephalitis were treated with both AEDs and immunotherapy (NMDAR 93%, GABABR 81%). This percentage tended to be lower in patients with anti-LGI1 encephalitis (71%, p = 0.051). Among anti-LGI1 encephalitis patients, more were treated with immunotherapy (91%) than with AEDs (80%). The median treatment delay between symptom onset and start of immunotherapy was 30 days (IQR 11–93), which was highest in the anti-LGI1 group (median of 96 days, IQR 48–290, p < 0.0001). Patients with anti-LGI1 encephalitis and focal seizures had a longer treatment delay (p = 0.007) than patients without focal seizures, while this delay was not observed in patients with anti-LGI1 encephalitis and FBDS (p = 0.20).\n\nSeizure freedom and treatment effects\n\nFigures 1–3 visualize timelines of all patients with epileptic seizures per antibody. Seizure freedom was achieved in 89% of all 110 patients. Of these 98 patients, 14% (n = 14) achieved seizure freedom while using only AEDs, while in 52 patients seizure freedom was achieved shortly after the start of immunotherapy (53%). Comparing the 68 patients receiving both AEDs and immunotherapy before seizure freedom was reached, the chance to achieve seizure freedom was higher after the use of immunotherapy than after the use of AEDs (immunotherapy n = 44, AEDs n = 3, p < 0.0001). This also applied for the groups separately (LGI1, p = 0.0001; NMDAR, p = 0.0005; GABABR, p = 0.013).\n\nFigure 1 Timelines (in days) of anti–leucine-rich glioma-inactivated 1 encephalitis patients with epileptic seizures\n\nThe percentages shown on the left correspond to patients (1) reaching seizure freedom after the use of immunotherapy (green), (2) reaching seizure freedom probably after the use of immunotherapy (triple green), (3) reaching seizure freedom after the use of antiepileptic drugs (AEDs) (red), (4) reaching seizure freedom probably after the use of AEDs (double red), (5) who could not be categorized (gray stripes), and (6) who did not reach seizure freedom (black dots). If patients were treated with another immunomodulating treatment >1 month after the initial treatment (for example, IV immunoglobulin after prednisolone), this is shown as a new blue square. Treatment with an additional AED or dosage increase after >1 month is shown as a second purple diamond. Relapses are only shown if patients had seizures. Median time of follow-up from onset was 33 months (interquartile range [IQR] 19–52, range 8–119). Median time of seizure freedom was 23 months (IQR 14–40, range 4–102). The median interval between start of AEDs and start of immunotherapy was 57 days (IQR 27–152). **Timeline of the only patient who developed epilepsy after resolved encephalitis. The symbols in this timeline are not fitted to scale. The onset of seizures was in 2009, the patient was treated with prednisone (and AEDs), leading to reversibility of cognitive signs, but he still has temporal epilepsy. IT = immunotherapy.\n\nFigure 2 Timelines (in days) of anti–NMDA receptor encephalitis patients with epileptic seizures\n\nSee legend of figure 1. Median time of follow-up was 37 months (interquartile range [IQR] 15–59, range 1–149). Median time of seizure freedom was 31 months (IQR 15–58, range 4–129). The median interval between start of antiepileptic drugs (AEDs) and start of immunotherapy was 14 days (IQR 4–24). IT = immunotherapy.\n\nFigure 3 Timelines (in days) of anti–gamma-aminobutyric acid B-receptor encephalitis patients with epileptic seizures\n\nSee legend of figure 1. Median time of follow-up was 15 months (interquartile range [IQR] 9–21, range 0–109). Median time of seizure freedom was 15 months (IQR 9–20, range 5–100). The median interval between start of antiepileptic drugs (AEDs) and start of immunotherapy was 10 days (IQR 7–28). IT = immunotherapy.\n\nThe median time to achieve seizure freedom after the start of AEDs was 59 days (IQR 27–160), and 28 days from start of immunotherapy (IQR 9–71, p < 0.0001). This decrease in days to seizure freedom after the use of immunotherapy was observed in all 3 syndromes (LGI1, p < 0.0001; NMDAR, p < 0.0001; GABABR, p = 0.001).\n\nSeizure freedom was achieved faster in women than in men (p < 0.0001), attributed to patients with anti-NMDAR encephalitis (p = 0.038). No differences were observed in days to seizure freedom between patients with paraneoplastic18 (n = 27) or nonparaneoplastic encephalitis (n = 83; p = 0.085). In patients with focal seizures, it took longer to achieve seizure freedom (p < 0.0001), while presence of tonic-clonic seizures did not influence the interval to seizure freedom (p = 0.081). In patients with LGI1 antibodies, the presence of FBDS did not shorten the interval to seizure freedom (p = 0.20).\n\nEleven patients did not reach seizure freedom. Ten patients had died, due to the encephalitis, before reaching seizure freedom, while one patient with anti-LGI1 encephalitis (3% of surviving patients with seizures and anti-LGI1 encephalitis) developed temporal epilepsy after resolved encephalitis. Median time of seizure freedom in AIE patients (after initial episode or last relapse) was 22 months (IQR 14–45, range 4–129). Fourteen of these patients (14%) were still using AED, while seizure-free. We have evaluated the proportion of patients who continued to have seizures at 6, 12, and 24 months after the initiation of immunotherapy (figure 4). At 6 months, seizure freedom was achieved in 79% of patients; of these 73 patients, 38 (52%) still used AEDs. At 12 months, 96% of patients had reached seizure freedom, of whom 34% still used AEDs while seizure-free. At 24 months, only one patient had developed epilepsy after resolved encephalitis (2%); the other 46 patients (98%) were seizure-free, among them 4 (9%) treated with AEDs. Fourteen patients developed a relapse with epileptic seizures within these 2 years (7 while using AED), and 12 became seizure-free again within days or weeks after restarting immunotherapy.\n\nFigure 4 Evaluation of the patients at risk to develop epilepsy after resolved encephalitis at 6, 12, and 24 months after the initiation of immunotherapy\n\nThe figure shows the cumulative percentages of the patients who reached or did not reach seizure freedom and the use of antiepileptic drugs (AEDs). Patients with a relapse less than 3 months before the time point at 6, 12, or 24 months, or with a relapse at 6, 12, or 24 months, are also shown in the figure. Fourteen patients developed a relapse with epileptic seizures within 24 months after the start of immunotherapy, in 7 of them despite continuous AED treatment. At relapse, the median seizure duration was 12 days (interquartile range [IQR] 4–29, range 3–92). Eleven of these 14 patients became seizure-free within days or weeks after restarting immunotherapy, 2 patients became seizure-free after 3 months, and 1 patient developed epilepsy after resolved encephalitis.\n\nAED effects and side effects\n\nPrescribed AEDs were levetiracetam (66%), valproic acid (53%), carbamazepine (32%), phenytoin (30%), clobazam (15%), lacosamide (7%), oxcarbazepine (6%), and lamotrigine (5%). Topiramate and phenobarbital were only used sporadically.\n\nResponses to these most prescribed AEDs and side effects are visualized in figure 5. Although some response was seen in all 3 groups, seizure freedom was only infrequently achieved. Carbamazepine appeared to have the best effect to reduce focal seizure frequency in anti-LGI1 encephalitis (figure 5D), while FBDS hardly responded to AEDs (figure 5E). In those anti-LGI1 patients treated with both levetiracetam and carbamazepine (n = 15), carbamazepine appeared more effective to reduce seizure frequency than levetiracetam (p = 0.031).\n\nFigure 5 Response percentages of most prescribed antiepileptic drugs (AEDs) and side effects\n\nResponse percentages of most prescribed AEDs and side effects in patients with (A) anti–gamma-aminobutyric acid B-receptor (GABABR), (B) anti–NMDA receptor (NMDAR), or (C) anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis, (D) focal seizures in patients with anti-LGI1 encephalitis, and (E) faciobrachial dystonic seizures (FBDS) in patients with anti-LGI1 encephalitis.“Some effect” was scored if noted specifically as a considerable reduction of seizures. In some patients, responses to specific AEDs were not assessable, due to concomitant use of immunotherapy or missing data. *A total of 20/21 patients with anti-GABABR encephalitis were treated with levetiracetam (LEV) (n = 16) or valproic acid (VPA) (n = 15), 11 patients were treated with both LEV and VPA. Responses of 2 patients treated with LEV were not assessable. **A total of 40/42 patients with anti-NMDAR encephalitis were treated with LEV (n = 28), VPA (n = 24), or carbamazepine (CBZ) (n = 10); in 17 patients, these AEDs were combined. Responses of seizures of 2 patients treated with VPA, 7 patients treated with LEV, and 4 patients treated with CBZ were not assessable. ***A total of 37 patients with anti-LGI1 encephalitis were treated with LEV (n = 29), VPA (n = 19), or CBZ (n = 22); in 25 patients, combinations of these AEDs were used. Responses of seizures of 4 patients treated with VPA, 6 patients treated with LEV, and 1 patient treated with CBZ were not assessable. Comparing patients treated with both LEV and CBZ (most prescribed, n = 15), CBZ was more effective (p = 0.031). In the LGI1 group, only 4 patients were treated with oxcarbazepine, 1 patient reached seizure freedom, 1 patient showed some effect, and 2 had no effect. Treatment responses of patients with anti-LGI1 encephalitis are also shown for focal seizures (D) and FBDS (E). FBDS hardly responded to VPA, LEV, or CBZ, while focal seizures responded somewhat better to carbamazepine.\n\nSide effects were frequently reported by patients with anti-LGI1 encephalitis (37%), and less by patients with anti-NMDAR (18%) and anti-GABABR (15%) encephalitis. Patients with LGI1 antibodies frequently had a rash by the use of carbamazepine (7/22, 32%). Most reported side effects by the use of valproic acid were memory deterioration (n = 3) and tremor (n = 2). Side effects of levetiracetam were rash (n = 3) and serious behavioral changes (n = 14; 19%), including 2 patients with anti-LGI1 encephalitis with severe psychotic behavior and suicidal thoughts.\n\nDiscussion\n\nThis nationwide observational cohort study evaluates seizure responses to immunotherapy and AEDs in patients with anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. We show that seizure freedom is achieved faster and more frequently after the use of immunotherapy than after the use of AEDs. In some patients, AEDs might decrease seizure frequency or lead to seizure freedom, but the effect is limited and incomparable to the effect of immunotherapy. After immunotherapy, the development of epilepsy after resolved encephalitis is rare in our cohort of AIE patients treated with immunotherapy.\n\nThese results emphasize the usefulness of immunotherapy in the treatment of epileptic seizures with an immune etiology caused by extracellular neuronal antibodies. In all groups there was a clear decrease in days to seizure freedom after the use of immunotherapy. It is customary to start AEDs before immunotherapy, so only comparing intervals between start of different treatments and seizure freedom would not be entirely fair. To avoid this confounding, we in addition compared the effects of AEDs and immunotherapy in patients who used both, and in which the responses to the individual treatment could be determined. This showed a clear preference for immunotherapy, which is in line with prior research in anti-LGI1 encephalitis, showing the positive effects of early immunotherapy on epileptic seizures and cognition.5,19\n\nThe effects of different treatment options were visualized (figures 1–3), showing that seizure freedom was frequently preceded directly by the initiation of immunotherapy and that patients treated earlier on in disease course seemed to reach seizure freedom faster. This effect was most remarkable in patients with anti-LGI1 encephalitis, wherein almost half of the patients became seizure-free within a week after immunotherapy, while they had been refractory to AEDs for longer periods. We did not analyze the effects of tumor treatment separately, because it was always accompanied by immunotherapy. Yet, we visualized that in patients with paraneoplastic encephalitis, both tumor treatment and immunomodulation often preceded seizure freedom. Mechanistically, both immunotherapy and tumor treatment are causal treatments, while AEDs are symptomatic treatments.\n\nOur study shows that seizures of most patients were AED-resistant. Seizure freedom was achieved in the minority of patients while using only AEDs, and adjustments in treatment regimen or dosage increase of AEDs did not affect the chance to achieve seizure freedom. In addition, these patients often had a milder disease course without status epilepticus. The AED-resistant character of seizures is a confirmation of observations in other studies.6,19,20 In addition, the often accompanying (subtle) cognitive symptoms also favor treatment with immunotherapy. Therefore, it seems better to use AEDs only as add-on symptomatic treatment.\n\nAfter treating the acute phase of the encephalitis, the continued use of AEDs is debatable. In our study, AED therapy was successfully discontinued in most patients after resolution of encephalitis. Chronic AED use does not appear to be necessary in most AIE patients long term. This is in line with previous studies studying separate subtypes of AIE.5,9,20 Although mesiotemporal sclerosis has been described in 25%–50% of follow-up MRIs in patients with anti-LGI1 encephalitis, only a few develop epilepsy after resolved encephalitis.9,21 For this reason, some argue against the implementation of the term epilepsy with immune origin13 (new ILAE classification) in the acute phase, reserving this for the situation after the encephalitis has been treated.22 In addition, side effects of AEDs, like memory disturbances, might disturb recovery after AIE, especially in combination with other drugs influencing brain functions, questioning even more the necessity for long-term AED use. Finally, half the patients who experienced a clinical relapse with epileptic seizures developed this relapse despite using AEDs and almost all patients became seizure-free again within days or weeks after restarting immunotherapy. However, prospective studies comparing different treatments in the chronic disease phase are lacking.\n\nThe AED-resistant character of seizures and crucial role of immunotherapy in treatment of seizures stress the importance of considering AIE as cause of epileptic seizures in patients with acquired drug-resistant seizures. Due to increased awareness, patients with a fulminant disease course with coma and status epilepticus, most frequently caused by GABABR or NMDAR antibodies, are regularly diagnosed early on in disease course. On the other hand, almost a quarter of the patients with anti-LGI1 encephalitis did not have a full-blown encephalitis, but seizures with only subtle encephalitis signs, which were often unrecognized by referring physicians. The unrecognition leads to diagnostic and treatment delay.9 In our study, this is reflected by (1) the longest treatment delay, (2) the longest interval between start of AEDs and immunotherapy, (3) a lower percentage of patients treated with AEDs, and (4) the observation that the presence of focal seizures extends the time to seizure freedom. As FBDS have gained much attention, better recognition and earlier treatment are to be expected. A longer delay until diagnosis and appropriate treatment in those with focal seizures shows that we should also look beyond FBDS to reduce delays and improve outcomes.\n\nConcerning responses to most prescribed AEDs, in our cohort, physicians preferred the use of levetiracetam. However, patients often had serious behavioral changes and 2 patients with anti-LGI1 encephalitis developed a severe psychosis and suicidal thoughts. In addition, levetiracetam might exaggerate symptoms of AIE, especially behavioral disorders. Focal seizures of anti-LGI1 patients responded relatively better to carbamazepine, while FBDS hardly responded to any AED. Only a few patients were treated with oxcarbazepine, a drug with a comparable mechanism of action as carbamazepine. Individual results of treatment with oxcarbazepine seem promising and comparable to the effect of carbamazepine, but need confirmation in larger patient groups. Lacosamide, a similar drug, was only used infrequently and as add-on, therefore assessment of the effects was impossible. A recent study describes that only 10% of patients with voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase 65 (GAD65) antibodies reached seizure freedom by the use of specific AEDs.23 Carbamazepine, lacosamide, and oxcarbazepine led most frequently to seizure-free outcome, while levetiracetam was ineffective in all patients. This is in line with our results, but difficult to compare as not all VGKC complex antibodies are pathogenic24 and as the pathogenicity of anti-GAD65 is unclear (incomparable to the pathogenicity of antibodies to extracellular antigens).25\n\nSide effects were reported most frequently by patients with LGI1 antibodies, and less by the other patients, probably due to a more fulminant disease course in patients with anti-GABABR and anti-NMDAR encephalitis. One-third of patients with LGI1 antibodies treated with carbamazepine had a rash. Rash is a common side effect of carbamazepine and occurs most often in patients with specific proimmunogenic human leukocyte antigen (HLA) types.26 Recently, a strong correlation with specific HLA types (HLA DR7 and DRB4) was found in patients with LGI1 antibodies.27,28 Yet these types do not correspond to the HLA types of patients who are prone to rash by the use of carbamazepine. An alternative explanation for the high percentage of rash within the LGI1 group might be the rapid dosage increase because of frequent, drug-resistant seizures.\n\nAlthough this is the largest cohort, and a nationwide study, regarding seizure responses to different treatments in patients with AIE and epileptic seizures, there are some limitations associated with the retrospective design of this study. Concerning data collection, effects and side effects were not always accurately documented. Patients were treated with a variety of AEDs and immunotherapies, and not per protocol, so comparisons are more difficult. However, the visualization of individual data in timelines is convincing that the differences between effects of AEDs and immunotherapy are real. We were not able to compare different treatment regimens (different AEDs and immunotherapies) due to small group sizes. Especially side effects are difficult to evaluate systematically in a retrospective design. Cognitive decline and behavioral disorders are hallmark symptoms of AIE, making it more difficult to categorize symptoms as disease progression or side effects of treatment. In addition, severe disease courses with coma and long-term intensive care stay make a proper evaluation of treatment effects (and side effects) difficult. Nevertheless, by treating these patients and by interviewing most patients, relatives, and treating physicians, important effects and side effects were still assessable and results from this study may help to compose treatment recommendations.\n\nWe would suggest using AEDs with sodium channel blocking properties (like carbamazepine or potentially oxcarbazepine) as first add-on next to immunotherapy in the symptomatic treatment of patients with anti-LGI1 encephalitis and seizures as it seems to have at least some effect in reducing focal seizures. However, due to the frequent occurrence of rash, often leading to discontinuation of therapy, it is essential to be cautious with rapid dosage increase. On the other hand, levetiracetam seems not preferable in the treatment of autoimmune epileptic seizures as the effects are limited and it can induce or exaggerate serious behavioral disorders.\n\nFrom this nationwide study, we can conclude that immunotherapy is most important in the treatment of epileptic seizures in patients with anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. The overall effect of AEDs in the symptomatic treatment of epilepsy in these patients is limited and antibody-dependent. Specific AEDs should be considered to use as add-on therapy to control seizures, but not as primary and long-term treatment.\n\nAcknowledgment\n\nThe authors thank the patients for their participation; all referring physicians, especially Prof. Dr. F.S.S. Leijten, Dr. J.A.E. van Asseldonk, and Dr. P.W. Wirtz; and Esther Hulsenboom and Mariska Nagtzaam for technical assistance.\n\nAuthor contributions\n\nM.A.A.M. de Bruijn: study design, acquisition of data, statistical analysis, interpretation of data, draft of the manuscript. A. van Sonderen: acquisition of data, revision of manuscript for content. M.H. van Coevorden-Hameete: acquisition of data, revision of manuscript for content. A.E.M. Bastiaansen: acquisition of data, revision of manuscript for content. M.W.J. Schreurs: acquisition of data, revision of manuscript for content. R.P.W. Rouhl: acquisition of data, revision of manuscript for content. C.A. van Donselaar: acquisition of data, revision of manuscript for content. M.H.J.M. Majoie: acquisition of data, revision of manuscript for content. R.F. Neuteboom: acquisition of data, revision of manuscript for content. P.A.E. Sillevis Smitt: acquisition of data, revision of manuscript for content. R.D. Thijs: acquisition of data, interpretation of data, revision of manuscript for content. M.J. Titulaer: study design, study supervision, interpretation of data, statistical analysis, revision of manuscript for content.\n\nStudy funding\n\nM.J.T. was supported by an ErasmusMC fellowship, has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), from the Dutch Epilepsy Foundation (NEF, project 14–19), and from ZonMw (Memorabel program).\n\nDisclosure\n\nM. de Bruijn, A. van Sonderen, M.H. van Coevorden-Hameete, A.E.M. Bastiaansen, M.W.J. Schreurs, R.P.W. Rouhl, C.A. van Donselaar, M.H.J.M. Majoie, and R.F. Neuteboom report no disclosures relevant to the manuscript. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. R.D. Thijs reports no disclosures relevant to the manuscript. M.J. Titulaer received research funds for serving on a scientific advisory board of MedImmune LLC and a travel grant for lecturing in India from Sun Pharma, India; has filed a patent for methods for typing neurologic disorders and cancer and devices for use therein; and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, and an unrestricted research grant from Euroimmun AG. Go to Neurology.org/N for full disclosures.\n\nGlossary\n\nAED antiepileptic drug\n\nAIE autoimmune encephalitis\n\nFBDS faciobrachial dystonic seizures\n\nGABABR gamma-aminobutyric acid B-receptor\n\nGAD65 glutamic acid decarboxylase 65\n\nHLA human leukocyte antigen\n\nILAE International League Against Epilepsy\n\nIQR interquartile range\n\nLGI1 leucine-rich glioma-inactivated 1\n\nmRS modified Rankin Scale\n\nNMDAR NMDA receptor\n\nVGKC voltage-gated potassium channel\n\nEditorial, page 877\n==== Refs\nReferences\n\n1. Dalmau J , Tüzün E , Wu HY , et al Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61 :25–36.17262855\n2. Irani SR , Michell AW , Lang B , et al Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69 :892–900.21416487\n3. Titulaer MJ , McCracken L , Gabilondo I , et al Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12 :157–165.23290630\n4. Lancaster E , Lai M , Peng X , et al Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9 :67–76.19962348\n5. Irani SR , Stagg CJ , Schott JM , et al Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013;136 :3151–3162.24014519\n6. Hoftberger R , Titulaer MJ , Sabater L , et al Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81 :1500–1506.24068784\n7. Vincent A , Irani SR , Lang B The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr Opin Neurol 2010;23 :144–150.20164770\n8. Gresa-Arribas N , Titulaer MJ , Torrents A , et al Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13 :167–177.24360484\n9. van Sonderen A , Thijs RD , Coenders EC , et al Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 2016;87 :1449–1456.27590293\n10. van Coevorden-Hameete MH , de Bruijn MA , et al Autoantibodies to KCTD16 mark the presence of a tumor in patients with GABAb receptor encephalitis. Brain (in press 2019). doi: 10.1093/brain/awz094.\n11. van Sonderen A , Ariño H , Petit-Pedrol M , et al The clinical spectrum of Caspr2 antibody-associated disease. Neurology 2016;87 :521–528.27371488\n12. Fisher RS , Acevedo C , Arzimanoglou A , et al ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55 :475–482.24730690\n13. Scheffer IE , Berkovic S , Capovilla G , et al ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58 :512–521.28276062\n14. Trinka E , Cock H , Hesdorffer D , et al A definition and classification of status epilepticus: report of the ILAE task force on classification of status epilepticus. Epilepsia 2015;56 :1515–1523.26336950\n15. Kwan P , Arzimanoglou A , Berg AT , et al Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51 :1069–1077.19889013\n16. Fisher RS , Cross JH , French JA , et al Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58 :522–530.28276060\n17. van Swieten JC , Koudstaal PJ , Visser MC , Schouten HJ , van Gijn J Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19 :604–607.3363593\n18. Graus F , Titulaer MJ , Balu R , et al A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15 :391–404.26906964\n19. Thompson J , Bi M , Murchison AG , et al The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141 :348–356.29272336\n20. Liu X , Yan B , Wang R , et al Seizure outcomes in patients with anti-NMDAR encephalitis: a follow-up study. Epilepsia 2017;58 :2104–2111.29098690\n21. Finke C , Prüss H , Heine J , et al Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74 :50–59.27893017\n22. Spatola M , Dalmau J Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Curr Opin Neurol 2017;30 :345–353.28234800\n23. Feyissa AM , López Chiriboga AS , Britton JW Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm 2017;4 :e353.28680914\n24. van Sonderen A , Schreurs MW , de Bruijn MA , et al The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86 :1692–1699.27037230\n25. Gresa-Arribas N , Arino H , Martinez-Hernandez E , et al Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One 2015;10 :e0121364.25774787\n26. Grover S , Kukreti R HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet Genomics 2014;24 :94–112.24336023\n27. Kim TJ , Lee ST , Moon J , et al Anti-LGI1 encephalitis is associated with unique HLA subtypes. Ann Neurol 2017;81 :183–192.28026029\n28. van Sonderen A , Roelen DL , Stoop JA , et al Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4. Ann Neurol 2017;81 :193–198.28026046\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0028-3878",
"issue": "92(19)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D000927:Anticonvulsants; D002648:Child; D004660:Encephalitis; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D018079:Receptors, GABA; D012640:Seizures; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e2185-e2196",
"pmc": null,
"pmid": "30979857",
"pubdate": "2019-05-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23290630;27893017;21416487;28680914;27590293;24014519;25774787;28026029;24068784;19889013;24730690;24360484;26336950;27037230;27371488;28276060;17262855;19962348;28026046;28276062;29098690;26906964;24336023;3363593;29272336;28234800;20164770",
"title": "Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.",
"title_normalized": "evaluation of seizure treatment in anti lgi1 anti nmdar and anti gababr encephalitis"
} | [
{
"companynumb": "NL-MYLANLABS-2019M1088967",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Zygomycosis is an angioinvasive fungal infection with a high mortality rate. Cutaneous zygomycosis is the second most common form of the disease, typically characterized by necrotic eschars in an immunocompromised host. We report an unusual case of superficial intertrigo resistant to conventional therapies caused by Mucor circinelloides in a patient with HIV and diabetes.",
"affiliations": "Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "McMahon|Devon E|DE|0000-0002-3649-9208;Hysell|Kristen|K|;Montgomery|Mary|M|;Frangos|Jason|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa043",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa043\nofaa043\nID Case\nSuperficial Cutaneous Zygomycosis Presenting as Resistant Intertrigo: A Case Report\nhttp://orcid.org/0000-0002-3649-9208McMahon Devon E 1 Hysell Kristen 2 Montgomery Mary 2 Frangos Jason 1 1 \nDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA\n2 \nDepartment of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA\nCorrespondence: D. McMahon, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115 (devon_mcmahon@hms.harvard.edu).\n2 2020 \n07 2 2020 \n07 2 2020 \n7 2 ofaa04305 12 2019 05 2 2020 24 2 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nZygomycosis is an angioinvasive fungal infection with a high mortality rate. Cutaneous zygomycosis is the second most common form of the disease, typically characterized by necrotic eschars in an immunocompromised host. We report an unusual case of superficial intertrigo resistant to conventional therapies caused by Mucor circinelloides in a patient with HIV and diabetes.\n\ndermatomycosesintertrigoMucor circinelloidesmucormycosisposaconazoleUnited States of Americazygomycosis\n==== Body\nCASE REPORT\nA man in his 60s with a history of well-controlled HIV (CD4 count 553 cells/µL, viral load undetectable) and type 2 diabetes (HgbA1c 8.8%) presented with foul-smelling, pruritic, erythematous plaques and satellite pustules over his bilateral axillae, medial thighs, inguinal folds, and scrotum (Figure 1). Over the previous 3 years, the patient was seen by multiple providers for a presumed diagnosis of candidal, dermatophytic, and/or polymicrobial intertriginous rash. His symptoms failed to improve after multiple topical antifungal agents, extended courses of fluconazole, oral antibiotics, topical clindamycin, and topical corticosteroids. A punch biopsy of the medial thigh showed skin acanthosis, hyperkeratosis, and florid intracorneal bacterial overgrowth.\n\nFigure 1. Intertriginous rash before treatment. A) Erythematous plaque over axilla. B) Erythematous plaque over inguinal fold with satellite pustules.\n\nA fungal culture from a swab of the inguinal crease revealed zygomycetes, and 2 repeat skin biopsies did not reveal invasive fungal infection. He was empirically started on oral posaconazole 400 mg twice daily, chlorhexidine washes, and topical clindamycin 1% lotion. The isolate was sent to the South Texas Reference Laboratory for identification and susceptibility testing. Identification of the isolate by combined phenotypic characterization and DNA sequencing revealed only Mucor circinelloides. Minimum inhibitory concentrations (MICs) were provided for amphotericin B (0.03 mcg/mL), posaconazole (0.5 mcg/mL), itraconazole (0.5 mcg/mL), and isavuconazole (8 mcg/mL), although there are no established breakpoints for interpretation. After 2 months of posaconazole therapy, he had complete resolution of his intertrigo and associated symptoms (Figure 2).\n\nFigure 2. Intertriginous rash after treatment. A) Complete resolution of axillary plaque after treatment with oral posaconazole. B) Complete resolution of inguinal plaque after treatment with oral posaconazole.\n\nDISCUSSION\nZygomycosis is an increasingly reported infection in immunocompromised hosts, a concerning trend given that mortality exceeds 50% [1]. Zygomycoses are ubiquitous, saprophytic opportunistic fungal infections caused by the class Zygomycetes [1, 2]. Most human infections are caused by the order Mucorales; thus the terms mucormycosis and zygomycosis are used interchangeably. The most common genera include Rhizopus, Lichtheimia (formerly Absidia), and Mucor [1]. Zygomycosis classically occurs in patients with diabetes mellitus and has also been reported in patients with hepatic or renal failure, chronic infections (ie, HIV, tuberculosis), vascular access catheters, extensive burns, trauma, iron overload, prolonged voriconazole use, hematologic malignancies, and solid organ transplantation [2, 3]. The most frequent form of zygomycosis is rhinocerebral (34%–49%), followed by cutaneous (10%–22%), pulmonary (10%–20%), disseminated (6%–13%), and gastrointestinal (2%–11%) disease [1, 3].\n\nCutaneous zygomycosis is usually an ominous diagnosis, characterized by necrotic skin lesions due to the angioinvasive nature of the organism [4] The most commonly reported cutaneous zygomycosis species is Rhizopus oryaze in 47% to 85% of cases, followed by Lichtheimia corymbifera, Rhizomucor pusillus, and Saksenaea vasiformis [5]. Primary cutaneous zygomycosis is frequently precipitated by skin trauma, usually leading to a necrotic eschar with surrounding erythema and induration [1, 5]. The primary cutaneous form often progresses to invade the fascia, muscles, tendons, and bones [5]. Secondary cutaneous zygomycosis describes hematogenous spread of systemic infection to the skin. The most common form of secondary cutaneous zygomycosis arises when the rhinocerebral form of the disease spreads to the skin, classically causing a palpebral fistula and necrotic ulcer [1, 5].\n\nDiagnosis of zygomycetes is difficult and often delayed, though more rapid molecular identification techniques are increasingly being used [6, 7]. Histopathology classically demonstrates invasive nonseptate hyphae; however, the sensitivity of histologic tests for superficial cutaneous mycoses is not well described [3]. The cornerstone of treatment for cutaneous zygomycosis is surgical debridement and systemic antifungal therapy, most often with amphotericin B. For susceptible isolates, oral posaconazole can also be given [5].\n\n\nMucor species represent 16% of all reported cases of zygomycosis, with M. circinelloides and M. indicus being the most common species [8]. However, Mucor species have infrequently been reported as causing primary skin zygomycosis [9, 10]. A review by Khan et al. of 6 case reports of cutaneous zygomycosis caused by M. circinelloides revealed that all cases were related to suspected trauma, and most were associated with necrotic ulceration [11]. A literature search yielded only 1 report of zygomycosis confined to the cutaneous and subcutaneous layers: a patient reported by Wang et al. with an indolent large dull erythematous nodular and ulcerating plaque on the dorsum of the hand, which had been present for 17 years [12].\n\nThe unique case presented herein demonstrates M. circinelloides manifesting as erythematous plaques confined to the most superficial layers of the skin. Besides our case, we are not aware of other reports in the literature of any species of cutaneous zygomycosis presenting in a superficial, intertriginous distribution. Zygomycosis should be considered in the differential diagnosis of intertriginous rash resistant to conventional therapies.\n\nAcknowledgments\n\nFinancial support. None reported.\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nRoden MM , Zaoutis TE , Buchanan WL , et al. \nEpidemiology and outcome of zygomycosis: a review of 929 reported cases\n. Clin Infect Dis 2005 ; 41 :634 –53\n.16080086 \n2. \nPetrikkos G , Skiada A , Lortholary O , et al. \nEpidemiology and clinical manifestations of mucormycosis\n. Clin Infect Dis 2012 ; 54 (Suppl 1 ):S23 –34\n.22247442 \n3. \nJeong W , Keighley C , Wolfe R , et al. \nThe epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports\n. Clin Microbiol Infect 2019 ; 25 :26 –34\n.30036666 \n4. \nBen-Ami R , Luna M , Lewis RE , et al. \nA clinicopathological study of pulmonary mucormycosis in cancer patients: extensive angioinvasion but limited inflammatory response\n. J Infect 2009 ; 59 :134 –8\n.19576639 \n5. \nBonifaz A , Vázquez-González D , Tirado-Sánchez A , Ponce-Olivera RM \nCutaneous zygomycosis\n. Clin Dermatol 2012 ; 30 :413 –9\n.22682190 \n6. \nSchwarz P , Bretagne S , Gantier JC , et al. \nMolecular identification of zygomycetes from culture and experimentally infected tissues\n. J Clin Microbiol 2006 ; 44 :340 –9\n.16455881 \n7. \nYang M , Lee JH , Kim YK , et al. \nIdentification of mucorales from clinical specimens: a 4-year experience in a single institution\n. Ann Lab Med 2016 ; 36 :60 –3\n.26522761 \n8. \nAlvarez E , Sutton DA , Cano J , et al. \nSpectrum of zygomycete species identified in clinically significant specimens in the United States\n. J Clin Microbiol 2009 ; 47 :1650 –6\n.19386856 \n9. \nLu XL , Liu ZH , Shen YN , et al. \nPrimary cutaneous zygomycosis caused by Rhizomucor variabilis: a new endemic zygomycosis? A case report and review of 6 cases reported from China\n. Clin Infect Dis 2009 ; 49 :e39 –43\n.19566442 \n10. \nLu XL , Najafzadeh MJ , Dolatabadi S , et al. \nTaxonomy and epidemiology of Mucor irregularis, agent of chronic cutaneous mucormycosis\n. Persoonia 2013 ; 30 :48 –56\n.24027346 \n11. \nKhan ZU , Ahmad S , Brazda A , Chandy R \nMucor circinelloides as a cause of invasive maxillofacial zygomycosis: an emerging dimorphic pathogen with reduced susceptibility to posaconazole\n. J Clin Microbiol 2009 ; 47 :1244 –8\n.19171681 \n12. \nWang JJ , Satoh H , Takahashi H , Hasegawa A \nA case of cutaneous mucormycosis in Shanghai, China\n. Mycoses 1990 ; 33 :311 –5\n.2259372\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(2)",
"journal": "Open forum infectious diseases",
"keywords": "Mucor circinelloides; United States of America; dermatomycoses; intertrigo; mucormycosis; posaconazole; zygomycosis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa043",
"pmc": null,
"pmid": "32123691",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": "19566442;19576639;22682190;30036666;16080086;22247442;16455881;26522761;19171681;24027346;2259372;19386856",
"title": "Superficial Cutaneous Zygomycosis Presenting as Resistant Intertrigo: A Case Report.",
"title_normalized": "superficial cutaneous zygomycosis presenting as resistant intertrigo a case report"
} | [
{
"companynumb": "US-009507513-2005USA002531",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORHEXIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5-4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.",
"affiliations": "Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.;Division of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland.",
"authors": "Paiano|Sandra|S|0000-0002-0529-4875;Roosnek|Eddy|E|;Tirefort|Yordanka|Y|;Nagy-Hulliger|Monika|M|;Masouridi|Stavroula|S|;Levrat|Emmanuel|E|;Bernimoulin|Michael|M|;Huguet|Saadia|S|;Casini|Alessandro|A|;Matthes|Thomas|T|;Samii|Kaveh|K|;Passweg|Jakob R|JR|;Chalandon|Yves|Y|0000-0001-9341-8104",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2015/980924",
"fulltext": "\n==== Front\nBone Marrow ResBone Marrow ResBMRBone Marrow Research2090-29992090-3006Hindawi Publishing Corporation 10.1155/2015/980924Clinical StudyComparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies http://orcid.org/0000-0002-0529-4875Paiano Sandra Roosnek Eddy Tirefort Yordanka Nagy-Hulliger Monika Masouridi Stavroula Levrat Emmanuel Bernimoulin Michael Huguet Saadia Casini Alessandro Matthes Thomas Samii Kaveh Passweg Jakob R. http://orcid.org/0000-0001-9341-8104Chalandon Yves \n*\nDivision of Hematology, Geneva University Hospital and University of Geneva, Geneva, Switzerland*Yves Chalandon: yves.chalandon@hcuge.chAcademic Editor: Hans-Jochem Kolb\n\n2015 22 3 2015 2015 98092427 10 2014 6 1 2015 31 1 2015 Copyright © 2015 Sandra Paiano et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5–4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.\n==== Body\n1. Introduction\nAntithymocyte globulins (ATGs) are used as immunomodulatory agents for prevention and treatment of graft-versus-host disease (GvHD) [1] in allogeneic hematopoietic stem cell transplantation (alloHSCT), for prevention and treatment of solid organ graft rejection, for treatment of aplastic anemia, and occasionally for treatment of other autoimmune disorders [2, 3]. These polyclonal immunoglobulins are IgG preparations from rabbits immunized with human thymocytes (Thymoglobulin) or with the T-acute lymphoblastic leukemia cell line Jurkat (ATG-Fresenius, ATG-F) [4]. ATG depletes T lymphocytes by induction of apoptosis or complement-dependent lysis. Furthermore, it may add immune suppression by modulation of surface molecules mediating leukocyte/endothelium interactions, induction of B-cell apoptosis, interference with dendritic cells properties, induction of regulatory T cells, or induction of NK T cells [5].\n\nDifferences between safety and efficacy of different brands of ATG are not well understood and only few studies have addressed these questions [6–9].\n\nThe aim of this analysis was to compare the impact of these two rabbit polyclonal antilymphocyte globulins on outcome in alloHSCT after reduced intensity conditioning regimen (RIC) for hematological malignancies.\n\n2. Patients and Methods\nOur report is a retrospective study of 30 consecutive patients transplanted between 2007 and 2010 after RIC consisting of ATG in combination with fludarabine 30 mg/m2/day for 5 days and busulfan i.v. 3.2 mg/kg/day for 2 days or fludarabine 30 mg/m2/day for 5 days and melphalan 70 mg/m2/day for 2 days (Hodgkin disease patients only). In order to avoid cost containment measures, we alternated between treatment with Thymoglobulin 2.5 mg/kg/day from day 5 to day 3 before transplant and ATG-F 5 mg/kg/day from day 6 to day 2. Twelve patients were transplanted for AML, the others for undifferentiated acute leukemia [1], lymphoma [9], multiple myeloma [2], chronic myelomonocytic leukemia [3], myelodysplastic syndrome [2], or myelofibrosis [1]. Stem cells came from peripheral blood mononuclear cells for all patients except for one patient in the ATG-F group who received bone marrow. Immunosuppression consisted of cyclosporine 4 mg/kg/day in continued infusion, mycophenolate mofetil for 1 month, and methylprednisolone 1000 mg during the 2 days before transplantation. Sixteen patients received a graft T cell depleted with 20 mg alemtuzumab in vitro followed the next day by an infusion of 100 × 106 CD3/kg for related donors and 0.35 × 106 CD3/kg for unrelated donors [10]. Median followup was 3.3 (2.5–4.5) years with no significant difference between groups receiving different ATG. We reviewed patient age, gender, diagnosis, remission status at transplant, CMV serostatus, reason for RIC instead of standard conditioning, type of donor, use of T cell depletion with Campath (alemtuzumab), T lymphocyte add-back dose, blood group compatibility, and GvHD prophylaxis and found no differences between the two groups (Table 1).\n\n2.1. Outcomes\nOutcomes analyzed were toxicity (incidence of adverse events during infusion of ATG), graft failure, rejection, infectious complications (infectious complications leading to hospitalization, intravenous antibiotherapy, or antiviral treatment (excluding preemptive treatment for CMV reactivation without clinical infection)), effects on immune reconstitution, acute and chronic GvHD, treatment related mortality (TRM), relapse incidence, and overall survival. Immune reconstitution was assessed by CD3, CD4, and CD8 counts and immunoglobulin levels (IgG, IgA, and IgM).\n\n2.2. Statistical Analysis\nAppropriate parametric or nonparametric tests were used to compare groups for continuous or categorical variables. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meyer method [11]; the log-rank test was used for comparison. Cumulative incidence was used for relapse, TRM, and GvHD. Relapse was used as competing risk for TRM incidence and also for GvHD incidence.\n\n3. Results\n3.1. Toxicity\nThere was a tendency to a higher incidence of adverse events during the Thymoglobulin perfusion compared to ATG-F, P = 0.14 (Table 2). Chills and/or fever occurred in 7 patients (2 patients had fever, 2 had chills, 2 had fever and chills including 1 with arterial hypotension, and 1 had fever with osteoarticular pain) and acute hepatic cytolysis in one patient in the Thymoglobulin group. In the ATG-F group, osteoarticular pain occurred during 2 infusions, fever and chills during one, and chills during another infusion.\n\n3.2. Graft Take/Rejection\nTime to engraftment was similar in both groups, with neutrophils reaching >0.5 G/L at a median time of 17 days (7–21) in the ATG-F group and 17.5 days (11–22) in the Thymoglobulin group (P = 0.60). Neutrophils reached levels above 1.5 G/L at a median time of 19 days (10–22) in the ATG-F group and 18 days (12–24) in the Thymoglobulin group (P = 0.76). Thrombocytes reached levels above 20 G/L at a median of 8.5 days (0–25) in the ATG-F group and 10 days (0–85) in the Thymoglobulin group (P = 0.46) and were at 50 G/L at a median time of 13 days (0–35) in the ATG-F group and 12 days (0–40) in the Thymoglobulin group (P = 0.52). There was one graft failure in each group (Table 2). Two rejections occurred in the ATG-F group and 3 in the Thymoglobulin group with similar median times to rejection (ATG-F group, 48 days, range 39–57; Thymoglobulin, 39 days, range 28–72, P = 0.93).\n\n3.3. Infections\nThe number of patients suffering from severe infections after the period of aplasia in the two groups was similar (9 in the ATG-F group and 7 in the Thymoglobulin group, P = 0.46) (Table 2). They consisted mainly of respiratory tract infections and bacteremia and some patients suffered from more than one. CMV viremia reactivation occurred in 11 patients in the ATG-F group and in 10 in the Thymoglobulin group, P = 0.69 (Table 2). Owing to the preemptive treatment with ganciclovir or valganciclovir, no clinical infection occurred.\n\n3.4. Immune Reconstitution\nWe measured immune reconstitution by the number of CD4- and CD8-positive T cells and by dosage of serum immunoglobulins. At 1 year after transplantation, the number of CD4-positive T cells reached >200/uL in 3 patients treated with ATG-F and in 5 treated with Thymoglobulin (P = 1.00), >400/uL in 0 and 2 patients in the respective groups (P = 0.18). CD8 counts >300/uL were reached in 6 and 5 patients, respectively (P = 1.00). Eight patients in the ATG-F group and 7 patients in the Thymoglobulin group had an IgG level >5 g/L (P = 1.00) while the level of IgG, IgA, and IgM was normal in 5 and 4 patients, respectively (P = 1.00).\n\n3.5. GvHD\nThe cumulative incidence of acute GvHD (aGvHD) grades I–IV at day 100 was twice as high (53.3%, 95% CI 33.2–85.6%) in the ATG-F group as in the Thymoglobulin group (26.7%, 95% CI 11.5–61.7%) but this difference did not reach statistical significance, P = 0.23 (Table 2, Figure 1). Two GvHD grade I and 6 GvHD grade II occurred in the ATG-F group and 2 GvHD grade I, 1 grade II, 1 GvHD grade III, and 1 grade IV in the Thymoglobulin group. The cumulative incidence of mainly extensive chronic GvHD at 3 years was 13.3% (95% CI 3.7–48.5%) in the ATG-F group and 20.0% (95% CI 7.3–55.0%) in the Thymoglobulin group, P = 0.87 (Table 2).\n\n3.6. OS, DFS, TRM, and Relapse\nOS and DFS at 3 years were 46.4% (95% CI 28.4–64.4%) and 36.7% (95% CI 19.1–54.3%), respectively, (Figures 2(a)-2(b)), without statistical differences between both groups. At three years OS was 45.7 (95% CI 19.7–71.7%) and 46.7 (95% CI 20.7–72.7%), P = 0.97. At 3 years DFS was 40.0 (95% CI 14.8–65.2%) and 33.7 (95% CI 8.9–58.1%), P = 0.86, in the Thymoglobulin and ATG-F groups, respectively, (Figures 2(c)-2(d)).\n\nWe observed tendencies to a lower TRM and more relapses in the Thymoglobulin group but this did not reach statistical significance. Cumulative incidence of TRM at 3 years was 33.3%, 95% CI 16.3–68.2% in the ATG-F group, and 20%, 95% CI 7.3–55% in the Thymoglobulin group, P = 0.67 (Table 2). Cause of death was infection (3 in each group), relapse (3 in the ATG-F group and 4 in the Thymoglobulin group), GvHD (1 in each group), or hemorrhage (1 in the ATG-F group). The cumulative incidence of relapse at three years (ATG-F group 33.3%, 95% CI 16.3–68.2%, and Thymoglobulin group 40%, 95% CI 21.5–74.3%) was not statistically different, P = 0.55 (Table 2).\n\n4. Discussion\nWe have analyzed the outcome of two different rabbit polyclonal antilymphocyte globulins in alloHSCT after RIC for hematological malignancies.\n\nIn our small cohort of 30 patients, we did not find any statistically significant differences between the two groups regarding all parameters tested (i.e., toxicity, engraftment, infection rate, immune reconstitution, GvHD incidence, TRM, or DFS). Given the small groups analyzed, it is not possible to see if there are differences, even if there were some. However, tendency towards more relapse, less TRM, and less acute GvHD was noticed in the Thymoglobulin group. This may point to a more T cell depleting potential in the doses used.\n\nTo our knowledge, our study is the first to compare these two ATGs in alloHSCT for patients suffering from hematological malignancies. A single center retrospective Japanese study [6] comprising 3 patients receiving Thymoglobulin (2.5 mg/kg/day from day 5 to day 2 before transplant) and 4 receiving ATG-F (5 mg/kg/day from day 7 to day 3 before transplant) has compared these ATGs in alloHSCT for aplastic anemia. They noticed no acute GvHD grade ≥II, nor rejection, but they observed CMV reactivation in 3/3 patients who had received Thymoglobulin and in 2/4 of the ATG-F group. CD4 and CD8 lymphocytes recovered later in the Thymoglobulin group than in the ATG-F group (data based on values on day 60). These results suggested that Thymoglobulin had a stronger immunosuppressive effect than ATG-F. In our study, we confirmed these high rates of CMV reactivation (10/15 in the Thymoglobulin and 11/15 in the ATG-F group) but we did not see a difference in CD4 and CD8 lymphocyte recovery at one year.\n\nATG is used to prevent rejection after solid organ transplantation. Also here, some studies have reported a possible more immunosuppressive effect of Thymoglobulin. In a single center retrospective French study published in 2004, comprising 194 renal transplanted patients [7], 65 of whom received Thymoglobulin (2–5 mg/kg day 0 and 1-2 mg/kg days 1 to 4 after transplant) and 129 ATG-F (9 mg/kg day 0 and 3 mg/kg days 1 to 4 after graft), more CMV reactivation occurred in the Thymoglobulin than in the ATG-F group (37% versus 23%, P = 0.02). Furthermore, in the Thymoglobulin group more patients developed posttransplant malignancies (12.3% versus 3.9%, P = 0.01) and/or died (13.8 versus 3.9%; P = 0.005). An Italian single center prospective randomized trial in heart transplantation [8] with 20 patients in the Thymoglobulin group (2.5 mg/kg/day for 5 days after transplant) and 20 in ATG-F group (2.5 mg/kg/day for 7 days after transplant) found no difference in rejection and survival, but more CMV reactivations in the Thymoglobulin group (65% versus 30%; P = 0.002). Furthermore new CMV infections occurred only in the Thymoglobulin group (20%, P = 0.05). No secondary malignancies were observed (followup of 32.8 ± 8.9 months). By contrast, a Swiss single center prospective randomized study from 2002 [9] comparing Thymoglobulin 2.5 mg/kg days 1 to 5 after transplant (n = 26) and ATG-F 3–3.5 mg/kg days 1 to 5 after transplant (n = 24) in the induction treatment for heart transplantation found no difference in survival, acute rejection, or infection rate for patients followed one year.\n\nA more immunosuppressive effect of Thymoglobulin may be owed to a more efficient depletion of T cells. Twenty years ago, different preparations of horse and rabbit ATG have been compared [12], including Thymoglobulin and ATG-F, and the latter appeared to bind somewhat less efficiently to many of the surface antigens on T cells. However, another study showed no difference in T cell cytotoxicity of Thymoglobulin and ATG-F [13]. Hence, differences will be relatively small, also because the effective doses of both ATGs have been titrated to calibrate the risk of infection and taking the benefit against GvHD and graft failure [14–16].\n\n5. Conclusions\nIn conclusion, subject to the small groups analyzed, our study does not show any statistically significant differences between Thymoglobulin and ATG-F regarding all the parameters tested. It may therefore be worthwhile to compare more in depth these two antilymphocyte globulins, in a larger study, to ascertain whether the tendency to some difference shown in the literature is real or not. However due to the small number of patients in each group we cannot exclude a possible difference that may exist. In fact, if there are some, the choice of the product should be based on the specific properties of each one and so adapted to the patient risk status.\n\nAcknowledgments\nThe authors acknowledge the contribution of the medical and nursing staff of the 5FL+ ward of the Hematology Division and the Medical Day Care Unit of the Oncology Division of Geneva University Hospital. The authors also thank Corinne Charrin, Colette Grand, and Carole Dantin for their excellent technical assistance in the stem cell laboratory.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors' Contribution\nSandra Paiano, Jakob R. Passweg, and Yves Chalandon designed the study. Yordanka Tirefort, Monika Nagy-Hulliger, Stavroula Masouridi, Emmanuel Levrat, Michael Bernimoulin, Saadia Huguet, Alessandro Casini, Thomas Matthes, Kaveh Samii, and Eddy Roosnek contributed data and reviewed the paper. Sandra Paiano, Jakob R. Passweg, and Yves Chalandon analyzed the data. Sandra Paiano, Jakob R. Passweg, Eddy Roosnek, and Yves Chalandon wrote the paper.\n\nFigure 1 Cumulative incidence of aGvHD grades I–IV at day 100, split by different ATG, 53.3% (95% CI 33.2–85.6) in the ATG-F group, 26.7% (95% CI 11.5–61.7) in the Thymoglobulin group, P = 0.23.\n\nFigure 2 Three years (a) OS (46.4% (95% CI 28.4–64.4%)), (b) DFS (36.7% (95% CI 19.1–54.3%)), (c) OS split by different ATG (45.7 (95% CI 19.7–71.7%) in the Thymoglobulin group and 46.7 (95% CI 20.7–72.7%) in the ATG-F group, P = 0.97), and (d) DFS split by different ATG (40.0 (95% CI 14.8–65.2%) in the Thymoglobulin group and 33.7 (95% CI 8.9–58.1%) in the ATG-F group, P = 0.86).\n\nTable 1 Patients, conditioning, and graft characteristics.\n\nPatients, conditioning, and graft characteristics\tATG-F\tThymoglobulin\t\nP\n\t\n\nn = 15\t\nn = 15\t\nAge at transplant, median (range, years)\t59 (40–69)\t51 (22–68)\t0.49\t\nNumber of men, n (%)\t8 (53)\t9 (60)\t0.72\t\nGroup diagnosis, n (%)\t \t \t \t\n AML\t6 (40)\t6 (40)\t1.00\t\n MDS\t2 (13)\t0\t0.46\t\n CMML\t0\t3 (20)\t0.23\t\n MF\t1 (7)\t0\t1.00\t\n NHL/HD\t5 (33)\t4 (27)\t0.69\t\n MM \t1 (7)\t1 (7)\t1.00\t\n Undifferentiated AL \t0\t1 (7)\t1.00\t\nComplete remission at transplant, n (%)\t15 (100)\t13 (87)\t0.48\t\nCMV serostatus donor/recipient, n (%)\t \t \t \t\n Positive recipient \t11 (73)\t12 (80)\t0.67\t\n Positive donor \t7 (47)\t8 (53)\t0.72\t\nReason for RIC, n (%) \t \t \t \t\n Prior autologous SCT\t8 (53)\t8 (53)\t1.00\t\n Age\t4 (27)\t4 (27)\t1.00\t\n Other \t3 (20)\t3 (20)\t1.00\t\nChemotherapy agents, n (%)\t \t \t \t\n Fludarabine-busulfan \t13 (87)\t12 (80)\t0.67\t\n Fludarabine-melphalan\t2 (13)\t3 (20)\t1.00\t\nRelated donor, n (%)\t4 (27)\t5 (33)\t0.69\t\n HLA-identical\t4 (27)\t5 (33)\t0.69\t\nUnrelated donor, n (%)\t11 (73)\t10 (67)\t0.69\t\n 0 mismatch\t8 (53)\t6 (40)\t0.46\t\n ≥1 mismatch\t3 (20)\t4 (27)\t0.67\t\nMen donor, n (%)\t9 (60)\t13 (87)\t0.10\t\nSex mismatch in GvHD sense, n (%)\t4 (27)\t1 (7)\t0.33\t\nPartial T cell depletion, n (%)\t7 (47)\t9 (60)\t0.46\t\nT cell dose, median (range, 10E6 CD3/kg)\t5 (0.35–130)\t5 (0.35–100)\t0.78\t\nBlood group incompatibility, n (%)\t \t \t \t\n Major\t4 (27)\t4 (27)\t1.00\t\n Minor\t4 (27)\t5 (33)\t0.91\t\nPosttransplant immunosuppression, n (%) \t15 (100)\t15 (100)\t1.00\t\nTable 2 Complications.\n\nComplications \tATG-F\tThymoglobulin\t\nP\n\t\n\nn = 15\t\nn = 15\t\nAdverse effect of antilymphocyte globulin perfusion, n (%)\t4 (27)\t8 (53)\t0.14\t\n\n\n\t\nGraft failure, n (%)\t1 (7)\t1 (7)\t1.00\t\n\n\n\t\nRejection, n (%)\t2 (13)\t3 (20)\t1.00\t\n\n\n\t\nRelapse, n (%)\t5 (33)\t7 (47)\t0.46\t\n\n\n\t\nCumulative incidence of relapse at 3 years (%) \t33.3 (16.3–68.2)\t40 (21.5–74.3)\t0.55\t\n\n\n\t\nCMV reactivation, n (%)\t11 (73)\t10 (67)\t0.69\t\n\n\n\t\nSevere infection after aplasia, n patients (%)\t9 (60)\t7 (47)\t0.46\t\n\n\n\t\nRespiratory infections, n\n\t2 RSV \n1 Staph. aureus \n\npneumonia\t2 H1N1 influenza \n2 bacterial pneumonia \n1 invasive lung \naspergillosis\t \t\n\n\n\t\nBacteremia, n\n\t2 Staphylococcus \n\n1 Kytococcus schroeteri \n\t1 multiple \n(E. coli, Pseudomonas sp., Listeria monocytogenes)\t \t\n\n\n\t\nOther infections, n\n\t3 BK-virus cystitis \n1 Microsporidiosis \n3 E. coli urinary \n1 HHV-6 encephalitis \n2 genital HSV-1\t1 gastroenteritis \n1 acute middle otitis \n1 generalized aspergillosis \n1 large spectrum beta-lactamase \nenterobacteria urinary\t \t\n\n\n\t\nAcute GvHD grade I, n (%)\t2 (13)\t2 (13)\t1.00\t\n\n\n\t\nAcute GvHD grades II–IV, n (%)\t6 (40)\t3 (20)\t0.23\t\n\n\n\t\nCumulative incidence of aGvHD grades I–IV at day 100 (%) \t53.3 (33.2–85.6)\t26.7 (11.5–61.7)\t0.23\t\n\n\n\t\nChronic limited GvHD, n (%)\t0\t1 (7)\t1.00\t\n\n\n\t\nChronic extensive GvHD, n (%)\t4 (27)\t3 (20)\t0.67\t\n\n\n\t\nCumulative incidence of cGvHD at 3 years (%) \t13.3 (3.7–48.5)\t20.0 (7.3–55.0)\t0.87\t\n\n\n\t\nDeath, n (%)\t8 (53)\t8 (53)\t1.00\t\n\n\n\t\nTRM, cumulative incidence at 3 years (%) \t33.3 (16.3–68.2)\t20 (7.3–55)\t0.67\t\n\n\n\t\nOS, cumulative incidence at 3 years (%)\t46.7 (20.7–72.7)\t45.7 (19.7–71.7)\t0.97\t\n\n\n\t\nDFS, cumulative incidence at 3 years (%)\t33.7 (8.9–58.1)\t40.0 (14.8–65.2)\t0.86\n==== Refs\n1 Theurich S. Fischmann H. Chakupurakal G. Anti-thymocyte globulins for post-transplant graft-versus-host disease prophylaxis-A systematic review and meta-analysis Critical Reviews in Oncology/Hematology 2013 88 1 178 186 10.1016/j.critrevonc.2013.03.009 2-s2.0-84884146092 23561334 \n2 Gaber A. O. Monaco A. P. Russell J. A. Lebranchu Y. Mohty M. Rabbit antithymocyte globulin (Thymoglobulin): 25 Years and new frontiers in solid organ transplantation and haematology Drugs 2010 70 6 691 732 10.2165/11315940-000000000-00000 2-s2.0-77951052617 20394456 \n3 Lytton S. D. Denton C. P. Nutzenberger A. M. Treatment of autoimmune disease with rabbit anti-T lymphocyte globulin: clinical efficacy and potential mechanisms of action Annals of the New York Academy of Sciences 2007 1110 285 296 10.1196/annals.1423.030 2-s2.0-35748953121 17911443 \n4 Popow I. Leitner J. Majdic O. Assessment of batch to batch variation in polyclonal antithymocyte globulin preparations Transplantation 2012 93 1 32 40 10.1097/tp.0b013e31823bb664 2-s2.0-84655161865 22186936 \n5 Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond Leukemia 2007 21 7 1387 1394 10.1038/sj.leu.2404683 2-s2.0-34250777773 17410187 \n6 Terasako K. Sato K. Sato M. The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia Hematology 2010 15 3 165 169 10.1179/102453309X12583347113852 2-s2.0-77953566288 20557676 \n7 Ducloux D. Kazory A. Challier B. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study Transplantation 2004 77 7 1029 1033 10.1097/01.tp.0000116442.81259.60 2-s2.0-1942451757 15087766 \n8 de Santo L. S. Della Corte A. Romano G. Midterm results of a prospective randomized comparison of two different rabbit-antithymocyte globulin induction therapies after heart transplantation Transplantation Proceedings 2004 36 3 631 637 10.1016/j.transproceed.2004.02.053 2-s2.0-11144357187 15110616 \n9 Schnetzler B. Leger P. Völp A. Dorent R. Pavie A. Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients Transplant International 2002 15 6 317 325 10.1111/j.1432-2277.2002.tb00171.x 2-s2.0-0036933592 12072903 \n10 Chalandon Y. Roosnek E. Mermillod B. Waelchli L. Helg C. Chapuis B. Can only partial T-cell depletion of the graft before hematopoietic stem cell transplantation mitigate graft-versus-host disease while preserving a graft-versus-leukemia reaction? A prospective phase II study Biology of Blood and Marrow Transplantation 2006 12 1 102 110 2-s2.0-29844448554 10.1016/j.bbmt.2005.09.010 16399574 \n11 Kaplan E. L. Meier P. Nonparametric estimation from incomplete observations Journal of the American Statistical Association 1958 53 457 481 10.1080/01621459.1958.10501452 MR0093867 \n12 Bourdage J. S. Hamlin D. M. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry Transplantation 1995 59 8 1194 1200 10.1097/00007890-199504270-00020 2-s2.0-0029070615 7732566 \n13 Penack O. Fischer L. Gentilini C. The type of ATG matters—natural killer cells are influenced differentially by Thymoglobulin, Lymphoglobulin and ATG-Fresenius Transplant Immunology 2007 18 2 85 87 10.1016/j.trim.2007.05.001 2-s2.0-36048960487 18005849 \n14 Meijer E. Cornelissen J. J. Löwenberg B. Verdonck L. F. Antithymocyteglobulin as prophylaxis of graft failure and graft-versus-host disease in recipients of partially T-cell-depleted grafts from matched unrelated donors: a dose-finding study Experimental Hematology 2003 31 11 1026 1030 10.1016/s0301-472x(03)00204-2 2-s2.0-0142165064 14585365 \n15 Remberger M. Svahn B.-M. Mattsson J. Ringdén O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation Transplantation 2004 78 1 122 127 2-s2.0-3142733478 15257050 \n16 Ayuk F. Diyachenko G. Zabelina T. Comparison of two doses of antithymocyte globulin in patients undergoing matched unrelated donor allogeneic stem cell transplantation Biology of Blood and Marrow Transplantation 2008 14 8 913 919 10.1016/j.bbmt.2008.05.023 2-s2.0-47249106496 18640575\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-3006",
"issue": "2015()",
"journal": "Bone marrow research",
"keywords": null,
"medline_ta": "Bone Marrow Res",
"mesh_terms": null,
"nlm_unique_id": "101566202",
"other_id": null,
"pages": "980924",
"pmc": null,
"pmid": "25874131",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "20394456;15257050;17911443;16399574;18640575;18005849;17410187;15087766;20557676;22186936;14585365;15110616;12072903;23561334;7732566",
"title": "Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies.",
"title_normalized": "comparing two types of rabbit atg prior to reduced intensity conditioning allogeneic hematopoietic sct for hematologic malignancies"
} | [
{
"companynumb": "CH-SA-2015SA054291",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo define at the molecular level the vascular endothelial cell (VEC) injury characteristics of catastrophic antiphospholipid syndrome (CAPS) and to report successful therapeutic use of a VEC modulator, defibrotide.\n\n\nMETHODS\nWe describe a 55-year-old man with primary APS with an intractable prothrombotic state (CAPS) resistant to combined therapy with heparin, warfarin, aspirin, and dipyridamole. Treatment with defibrotide was conducted in the context of an investigational phase II protocol where the dose was regulated and individualized by disease/patient-specific molecular and clinical markers.\n\n\nRESULTS\nThe patient entered complete remission with defibrotide treatment. During treatment, dose dependent pharmacological actions of defibrotide and key stress markers for VEC injury were identified. Evidence of defibrotide's polypharmacology included downregulation of cytokines, notably tumor necrosis factor-alpha, as the earliest effect, cellular differentiation of VEC, possibly with direct regulatory effect over cellular genes, and the reversal of platelet consumption and prothrombotic state. Von Willebrand antigen levels were used as the sole marker to guide therapy.\n\n\nCONCLUSIONS\nThis case demonstrates effective remission of CAPS with defibrotide treatment. In contrast to theories that CAPS is triggered by ischemic and thrombotic tissue damage, these data present VEC injury as the primary and representative lesion of CAPS. The pathogenesis may involve concurrent impairment of different VEC functions. Achieving remission may require a polypharmacologic approach, represented here by use of defibrotide.",
"affiliations": "Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA.",
"authors": "Burcoglu-O'Ral|Arsinur|A|;Erkan|Doruk|D|;Asherson|Ronald|R|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D010975:Platelet Aggregation Inhibitors; D011089:Polydeoxyribonucleotides; C036901:defibrotide",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "29(9)",
"journal": "The Journal of rheumatology",
"keywords": null,
"medline_ta": "J Rheumatol",
"mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D002388:Catastrophic Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011089:Polydeoxyribonucleotides; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "2006-11",
"pmc": null,
"pmid": "12233899",
"pubdate": "2002-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment of catastrophic antiphospholipid syndrome with defibrotide, a proposed vascular endothelial cell modulator.",
"title_normalized": "treatment of catastrophic antiphospholipid syndrome with defibrotide a proposed vascular endothelial cell modulator"
} | [
{
"companynumb": "US-JAZZ-2018-US-007722",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEFIBROTIDE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Neutrophilic dermatoses include a heterogeneous group of entities. Uncommonly, they can accumulate aseptic neutrophilic abscesses in other tissues in addition to the skin. A 34-year-old female complained of a headache which was unresponsive to usual drugs. A TAC revealed an osteolytic lesion in the right parietal bone. The biopsy showed osteomyelitis. One year later, pyoderma gangrenosum appeared in the anterior aspect of both legs. The headache and the cutaneous lesions disappeared after treatment with oral prednisone. The bone involvement in the background of neutrophilic dermatoses is exceptional. Usually, it involves children in the context of chronic recurrent multiple osteomyelitis (CRMO). Only two cases have been described in adults. One of them was a 26-year-old woman who had had CRMO since childhood, and the other one in contiguity with the cutaneous lesions of pyoderma gangrenosum.",
"affiliations": "Sección de Dermatología, Hospital Dr. José Molina Orosa, Lanzarote, Provincia de Las Palmas, España. Electronic address: enric@aedv.es.;Servicio de Neurocirugía, Hospital Universitario de Gran Canaria Doctor Negrín, Provincia de Las Palmas, España.;Servicio de Patología, Hospital Universitario de Gran Canaria Doctor Negrín, Provincia de Las Palmas, España.;Servicio de Medicina Interna, Hospital Dr. José Molina Orosa, Lanzarote, Provincia de Las Palmas, España.",
"authors": "Piqué-Durán|Enric|E|;Morera Molina|Jesús|J|;Limeres-González|Miguel Ángel|MÁ|;Espejo-Gil|Ana María|AM|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.neucir.2020.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2529-8496",
"issue": null,
"journal": "Neurocirugia (English Edition)",
"keywords": "Aseptic osteomyelitis; Cranial lytic lesion; Dermatosis neutrofílica; Enfermedad neutrofílica; Lesión lítica craneal; Neutrophilic dermatoses; Neutrophilic disease; Osteomielitis aséptica; Pioderma gangrenoso; Pyoderma gangrenosum",
"medline_ta": "Neurocirugia (Astur : Engl Ed)",
"mesh_terms": null,
"nlm_unique_id": "101778588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33546980",
"pubdate": "2021-02-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cranial aseptic osteomyelitis associated with pyoderma gangrenosum.",
"title_normalized": "cranial aseptic osteomyelitis associated with pyoderma gangrenosum"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2022-02647",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditiona... |
{
"abstract": "The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue.",
"affiliations": "Institute of Legal Medicine, University Hospital Duesseldorf, Moorenstraße 5, 40225 Duesseldorf, Germany. Electronic address: evelyn.pawlik@uni-duesseldorf.de.;State Bureau of Criminal Investigation NRW, Criminal Scientific and Technical Institute, Völklinger Straße 49, 40221 Duesseldorf, Germany. Electronic address: hellmut.mahler@polizei.nrw.de.;Institute of Legal Medicine, University Hospital Duesseldorf, Moorenstraße 5, 40225 Duesseldorf, Germany. Electronic address: benno.hartung@med.uni-duesseldorf.de.;State Bureau of Criminal Investigation NRW, Criminal Scientific and Technical Institute, Völklinger Straße 49, 40221 Duesseldorf, Germany. Electronic address: gerd.plaesser@polizei.nrw.de.;Institute of Legal Medicine, University Hospital Duesseldorf, Moorenstraße 5, 40225 Duesseldorf, Germany. Electronic address: fortoxi@uni-duesseldorf.de.",
"authors": "Pawlik|Evelyn|E|;Mahler|Hellmut|H|;Hartung|Benno|B|;Plässer|Gerd|G|;Daldrup|Thomas|T|",
"chemical_list": "D013287:Illicit Drugs; D009294:Narcotics; D007978:Levamisole; D006919:Hydroxyzine; D008012:Lidocaine; D004110:Diltiazem; D010615:Phenacetin; D003042:Cocaine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "249()",
"journal": "Forensic science international",
"keywords": "Adulterants; Cocaine; Drug-related death; Lung tissue",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D001774:Blood Chemical Analysis; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine; D019970:Cocaine-Related Disorders; D004110:Diltiazem; D004340:Drug Contamination; D053593:Forensic Toxicology; D006801:Humans; D006919:Hydroxyzine; D013287:Illicit Drugs; D007978:Levamisole; D008012:Lidocaine; D059625:Liquid-Liquid Extraction; D008168:Lung; D013058:Mass Spectrometry; D009294:Narcotics; D010615:Phenacetin; D052616:Solid Phase Extraction",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "294-303",
"pmc": null,
"pmid": "25747329",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-related death: adulterants from cocaine preparations in lung tissue and blood.",
"title_normalized": "drug related death adulterants from cocaine preparations in lung tissue and blood"
} | [
{
"companynumb": "DE-BAUSCH-BL-2015-011971",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CODEINE"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of a woman with chronic hepatitis C and idiopathic thrombocytopenic purpura (ITP) who developed autoimmune hepatitis (AIH) during antiviral therapy with ledipasvir (LDV)/sofosbuvir (SOF). The onset of acute hepatitis rose two weeks after starting treatment with LDV/SOF when HCV-RNA tested negative, suggesting a link between rapid HCV clearance and de novo autoimmune diseases. Conclusion: This case report proposes new immunologic scenarios in patients with hepatitis C virus (HCV) with laboratory or clinical signs of autoimmunity during direct-acting antiviral (DAA) therapy.",
"affiliations": "Liver Unit and Center for Autoimmune Liver Diseases.;Clinical Investigation Laboratory.;Nephrology and Dialysis Unit.;Department of Pathology Humanitas Clinical and Research Center Rozzano Italy.;Liver Unit and Department of Biomedical Sciences Humanitas University Rozzano Italy.;Liver Unit and Department of Biomedical Sciences Humanitas University Rozzano Italy.",
"authors": "Covini|Giovanni|G|;Bredi|Elena|E|;Badalamenti|Salvatore|S|;Roncalli|Massimo|M|;Aghemo|Alessio|A|;Colombo|Massimo|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hep4.1248",
"fulltext": "\n==== Front\nHepatol CommunHepatol Commun10.1002/(ISSN)2471-254XHEP4Hepatology Communications2471-254XJohn Wiley and Sons Inc. Hoboken 10.1002/hep4.1248HEP41248Brief ReportBrief ReportsAutoimmune Hepatitis During Ledipasvir/Sofosbuvir Treatment of Hepatitis C: A Case Report Covini et al.Covini Giovanni , M.D.giovanni.covini@humanitas.it \n1\nBredi Elena \n2\nBadalamenti Salvatore \n3\nRoncalli Massimo \n4\nAghemo Alessio \n5\nColombo Massimo \n5\n\n1 \nLiver Unit and Center for Autoimmune Liver Diseases\n\n2 \nClinical Investigation Laboratory\n\n3 \nNephrology and Dialysis Unit\n\n4 \nDepartment of Pathology\nHumanitas Clinical and Research Center\nRozzano\nItaly\n\n5 \nLiver Unit and Department of Biomedical Sciences\nHumanitas University\nRozzano\nItaly\n* \nAddress Correspondence and Reprint Requests To:\n\nGiovanni Covini, M.D.\n\nLiver Unit and Center for Autoimmune Liver Diseases\n\nVia Manzoni, 56\n\nRozzano, 20089, Italy\n\nE‐mail: giovanni.covini@humanitas.it\n\nTel.: +39‐02‐8224‐4541\n25 9 2018 10 2018 2 10 10.1002/hep4.v2.101179 1183 23 2 2018 17 7 2018 © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nWe report the case of a woman with chronic hepatitis C and idiopathic thrombocytopenic purpura (ITP) who developed autoimmune hepatitis (AIH) during antiviral therapy with ledipasvir (LDV)/sofosbuvir (SOF). The onset of acute hepatitis rose two weeks after starting treatment with LDV/SOF when HCV‐RNA tested negative, suggesting a link between rapid HCV clearance and de novo autoimmune diseases. Conclusion: This case report proposes new immunologic scenarios in patients with hepatitis C virus (HCV) with laboratory or clinical signs of autoimmunity during direct‐acting antiviral (DAA) therapy.\n\n source-schema-version-number2.0component-idhep41248cover-dateOctober 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:01.10.2018Potential conflict of interest: Dr. Colombo advises and is on the speakers’ bureau for MSD and AbbVie. Dr. Aghemo is on the speakers’ bureau and received grants from Gilead, AbbVie, MSD, and Bristol‐Myers Squibb and is on the speakers’ bureau for Janssen. The other authors have nothing to report.\n==== Body\nAbbreviations\nAIHautoimmune hepatitis\n\nALTalanine aminotransferase\n\nANAanti‐nuclear antibody\n\nDAAdirect‐acting antiviral\n\nDILIdrug‐induced liver injury\n\nHCVhepatitis C virus\n\nIgMimmunoglobulin M\n\nITPidiopathic thrombocytopenic purpura\n\nLDVledipasvir\n\nPLTplatelet\n\nSOFsofosbuvir\n\nAIH is a rare disease that in the majority of patients occurs without any identifiable trigger. This is in contrast with patients who develop AIH as a consequence of exposure to medications, such as anti‐inflammatory molecules, anti‐tumor necrosis factor α monoclonal antibodies, and immune checkpoint inhibitors.1 In 2013, a coformulated oral regimen consisting of a nonstructural protein 5A (NS5A) inhibitor (LDV) and an NS5B nucleotide analog inhibitor (SOF) of the HCV became the standard of care to treat chronic infection with HCV genotypes 1 and 4 in adults and more recently in adolescents. Studies of antiviral therapy of HCV, while highlighting the safety and effectiveness of DAA regimens, have also reported sporadic episodes of adverse effects associated with immune dysregulation.2 We report the case of a woman with chronic hepatitis C and idiopathic thrombocytopenic purpura (ITP) who developed AIH during antiviral therapy with LDV/SOF.\n\nThe Case\nA 72‐year‐old woman with chronic hepatitis C genotype 1b, arterial hypertension, type 2 diabetes mellitus, and ITP, who was diagnosed on the basis of anti‐platelet glycoprotein Ia/IIa autoantibodies, was referred following the onset of acute hepatitis 2 weeks after starting treatment with LDV and SOF. Infection with HCV was diagnosed in 2002, but antiviral therapy was deferred to avoid worsening of severe ITP using interferon‐based regimens. Since 2002, the patient had been under biannual surveillance with liver enzyme values repeatedly testing normal. In 2016, hepatitis flared with serum alanine aminotransferase (ALT) of 160 U/L and aspartate aminotransferase (AST) of 135 U/L; these were associated with 1.2 mg bilirubin, a low platelet (PLT) count (100,000/mm3), and a low virus load (HCV‐RNA 520 IU/mL). Gamma‐glutamyltransferase, alkaline phosphatase, and gamma globulin levels were within the normal range (15%). A liver biopsy showed moderate portal‐based active hepatitis (grade 2) without interface or lobular activity consistent with chronic HCV infection, with moderate fibrosis (stage 3) according to a FibroScan value of 11 kPa. At that time, no signs of AIH were present and serum autoantibodies were not tested. The patient had been receiving insulin and carvedilol 6.25 mg twice a day for more than 15 years. At this point, the caregivers decided to start LDV/SOF therapy for HCV.\n\nAfter 2 weeks of antiviral therapy, ALT and AST flared to 923 U/L and 752 U/L, respectively, whereas serum markers of cholestasis were within the normal range and HCV‐RNA was undetectable. At this point, the PLT count dropped to 11,000/mm3, causing ecchymoses at the sites of insulin injection. The finding of an anti‐nuclear antibody (ANA) titer of 1:320 (immunofluorescence pattern not reported) led the caregivers to add on prednisone monotherapy 50 mg/day during the first month of antiviral therapy. Serum HCV‐RNA remained undetectable, ALT progressively fell to normal values, and PLTs rose to 210,000/mm3. Prednisone monotherapy was tapered down during the remaining weeks of antiviral therapy. Two weeks after completion of antiviral therapy when prednisone was dosed at 2.5 mg/day, ALT broke through to 250 U/L whereas HCV‐RNA remained undetectable and the PLT count fell to 65,000/mm3, a finding that caused prednisone monotherapy to be adjusted to 25 mg/day and led the patient to be referred to our center with a suspected diagnosis of AIH.\n\nOn physical examination, the patient showed no hepatosplenomegaly or skin ecchymoses. Serum markers of viral hepatitis, including hepatitis A virus immunoglobulin M (IgM), hepatitis B surface antigen, total hepatitis B core antibody, HCV‐RNA, hepatitis E virus IgM, herpes simplex DNA, cytomegalovirus IgM, and Epstein‐Barr virus DNA all tested negative; however, serum ANA was 1:80 speckled and the level of peripheral anti‐neutrophil cytoplasmic antibodies (p‐ANCA) was strongly positive (Fig. 1). Anti‐mitochondrial antibodies, anti‐smooth muscle antibodies, and anti‐liver/kidney microsome antibodies were negative. Gamma globulin levels were normal (16%), the PLT count was 135,000 /mm3, and the ALT value was 65 U/L. Liver biopsy demonstrated the presence of plasma cells clustering in areas of piecemeal necrosis, which along with an AIH score of 22 was strongly suggestive of AIH (Fig. 2).3 One year after completion of LDV/SOF therapy, the patient was still on 7.5 mg prednisone monotherapy, serum HCV‐RNA remained undetectable, and the ALT and PLT count were within the normal range (Fig. 3).\n\nFigure 1 Neutrophils and HEp‐2 cells stained by indirect immunofluorescence with patient serum. (A) Patient serum tested strongly positive for p‐ANCA (titer >1:320). (B) Patient serum tested weakly ANA positive (titer 1:80), showing a fine granular staining of nuclei.\n\nFigure 2 The liver biopsy is characterized by a moderate to marked portal chronic inflammatory infiltrate with continuous interface hepatitis (hematoxylin and eosin, magnification ×10). The inset (multiple myeloma oncogene 1/interferon regulatory factor 4 immunostaining, magnification ×40) highlights the presence of plasma cells depicted in a cluster in a portal space and as scattered elements spilling over the parenchyma.\n\nFigure 3 ALT levels and PLT count during 12 weeks of LDV/SOF therapy and 12 weeks of follow‐up. At the end of week 2 of LDV/SOF, ALT flared to 923 U/L, PLT count decreased to 11,000/mm3, and HCV‐RNA was undetectable. Following addition of prednisone 50 mg/day, ALT progressively normalized and HCV‐RNA remained undetectable. Two weeks after completion of antiviral therapy as prednisone was down‐dosed to 2.5 mg/day, ALT broke through to 250 U/L and PLT count decreased to 65,000 /mm3, requiring prednisone to be adjusted to 25 mg/day. Eight months from antiviral therapy cessation, ALT was normal and HCV‐RNA was undetectable while the patient was still being dosed with 7.5 mg prednisone daily.\n\nDiscussion\nLiver injury following exposure to medications, herbs, or other toxic substances stands as one of the most common causes of acute liver damage, yet a differential diagnosis between a drug‐induced liver injury (DILI) and an AIH is almost impossible to obtain in many patients.4 Differential diagnosis between those conditions is in fact often clouded by the appearance of immunologic markers, such as serum tissue autoantibodies and elevated immunoglobulin G levels, and overlapping histologic patterns of liver injury, particularly in patients with idiosyncratic DILI.3 Several lines of evidence indicate that AIH develops as a consequence of a loss of liver capacity for immune tolerance, an event that allows for an interaction between the liver, drugs, and antigens derived from the gut5, 6 and ultimately leads to chronic inflammation of the liver. One teaching example of this7 is patients with tuberculosis exposed to isoniazid who suffer a transient increase of liver enzymes followed by spontaneous recovery despite continued dosing with the offending drug. While this condition is considered a clinical adaptation reflecting the development of immune tolerance against isoniazid, some patients may mount a “defective adaptation” to the drug regimen, leading to development of a liver injury with continued exposure to the offending drug.8 Although this is particularly true in patients with idiosyncratic DILI who develop unpredictable, non‐dose‐related liver injury,9 it is worth mentioning that medications, such as oxyphenisatin, statin, nitrofurantoin, minocycline, chlometacin, and alpha‐methyl‐dopa, may trigger a liver injury that persists after drug discontinuation, suggesting that liver disease is caused by a true autoimmune reaction.10, 11\n\n\nCharacteristically, infection with HCV may trigger a variety of immune reactions, including onset of non‐organ‐specific autoantibodies, cryoglobulins, autoimmune dysthyroidism, arthralgias, myalgias, and lichen planus.12 Such a link between HCV and immune reactions has been a reason for deferring therapy with interferon of patients at risk of exacerbating a latent autoimmune disorder; this barrier has recently been lifted following the arrival of DAAs, which offered the opportunity to safely treat patients infected with HCV who present with various autoimmune phenomena.13, 14, 15, 16 Recently, a multidisciplinary consensus and evidence‐based recommendations on the management of HCV extrahepatic manifestations have been proposed that suggest considering DAA as first‐line treatment for HCV‐mixed cryoglobulinemia.13 Furthermore, many reported cases suggest that HCV eradication is often associated with the improvement of lichen planus,17 another HCV‐associated immunologic condition. The impact of DAA on other rheumatologic manifestations, such as Sjögren’s syndrome and arthralgia/myalgia, is lacking. Few reports show a DAA treatment for patients with HCV and autoimmune liver diseases. Interestingly, Sugiura et al.18 achieved a sustained virologic response (SVR) in a patient affected by HCV‐AIH overlap syndrome. In this scenario, DAA seems to be a safe and effective treatment in patients with HCV and immunologic disorders. However, some evidence suggests alterations of immune status are DAA induced. Kanda et al.2 treated 5 patients with HCV plus primary biliary cholangitis and 7 patients with HCV‐AIH overlap syndrome and achieved a 100% rate of SVR. Of the 7 patients with HCV‐AIH overlap syndrome, 3 received prednisone at baseline and 3 did not receive prednisone during DAA therapy; in 1 female patient with HCV‐AIH overlap syndrome plus cirrhosis who was treated with LDV/SOF, prednisone was not administered at baseline but was given after 8 weeks of liver chemistry abnormalities. Kanda et al. concluded that, in this category of patients, clinicians should pay special attention to acute exacerbation of liver diseases. Another example of immune imbalance induced by DAA therapy of HCV is the unexpected high rate of de novo or recurrent hepatocellular carcinoma (HCC) that has been reported in patients with HCV after DAA therapy19, 20 despite the co‐occurrence of such relevant confounding factors as heterogeneity of follow‐up, starting point of analysis, time lag between DAA initiation and HCC onset, and modalities of cancer therapy. To reconcile the anti‐HCV activity of DAAs with their potential to stimulate host immunity, it has been suggested that rapid elimination of HCV might favor a dysregulation of immune surveillance through a variety of mechanisms,21, 22, 23 with some evidence that HCC might preferentially develop in patients whose immune backgrounds are already affected prior to DAA exposure.\n\nConsidering that before DAA administration, the patient in this case report had persistently normal values of serum aminotransferases during 15 years of surveillance at biannual intervals, the onset of acute hepatitis 2 weeks after starting treatment with LDV/SOF when HCV‐RNA tested negative points to drug‐induced AIH as a culprit. Furthermore, even if serum autoantibodies were not tested before LDV/SOF therapy for HCV, baseline liver biopsy and blood tests ruled against the coexistence of chronic hepatitis C with AIH. On the other hand, the fact that our patient developed a concurrent ITP is consistent with AIH being frequently associated with extrahepatic autoimmune disorders, such as rheumatoid arthritis, Sjögren’s syndrome, and chronic thyroiditis. The association of ITP with AIH has been reported at a prevalence of around 2%,24 whereas it is a well‐documented complication of HCV infection, ranging from 3% to 20% depending on the geographic area.25 While the true origin of thrombocytopenia seen in our patient remains elusive, i.e., autoimmune‐associated versus virus‐associated ITP,25 we outline that its presence stands as a marker of autoimmunity that may herald development of autoimmune disease following a DAA‐driven imbalance of the immune system.\n\nAlthough firm experimental evidence supporting a link between rapid HCV clearance and de novo autoimmune diseases is still lacking, the patient described here with chronic hepatitis C associated with ITP might well represent a candidate predisposed to develop AIH with rapid suppression of HCV with DAA therapy. This case report further emphasizes the need for patients with either laboratory or clinical signs of autoimmunity to be carefully monitored for the risk of developing AIH during DAA therapy of HCV.\n==== Refs\nReferences\n1 \n\nCastiella \nA \n, \nZapata \nE \n, \nLucena \nMI \n, \nAndrade \nRJ \n. Drug‐induced autoimmune liver disease: a diagnostic dilemma of an increasingly reported disease . World J Hepatol \n2014 ;6 :160 ‐168 .24799984 \n2 \n\nKanda \nT \n, \nYasui \nS \n, \nNakamura \nM \n, \nNakamoto \nS \n, \nTakahashi \nK \n, \nWu \nS \n, et al. Interferon‐free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis . Oncotarget \n2018 ;9 :11631 ‐11637 .29545925 \n3 \n\nAlvarez \nF \n, \nBerg \nPA \n, \nBianchi \nFB \n, \nBianchi \nL \n, \nBurroughs \nAK \n, \nCancado \nEL \n, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis . J Hepatol \n1999 ;31 :929 ‐938 .10580593 \n4 \n\nKullak‐Ublick \nGA \n, \nAndrade \nRJ \n, \nMerz \nM \n, \nEnd \nP \n, \nBenesic \nA \n, \nGerbes \nAL \n, et al. Drug‐induced liver injury: recent advances in diagnosis and risk assessment . Gut \n2017 ;66 :1154 ‐1164 .28341748 \n5 \n\nKnolle \nPA \n, \nGerken \nG \n. Local control of the immune response in the liver . Immunol Rev \n2000 ;174 :21 ‐34 .10807504 \n6 \n\nWilliams \nGM \n, \nIatropoulos \nMJ \n. Alteration of liver cell function and proliferation: differentiation between adaptation and toxicity . Toxicol Pathol \n2002 ;30 :41 ‐53 .11890475 \n7 \n\nMitchell \nJR \n, \nLong \nMW \n, \nThorgeirsson \nUP \n, \nJollow \nDJ \n. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy . Chest \n1975 ;68 :181 ‐190 .1080096 \n8 \n\nWatkins \nPB \n. Idiosyncratic liver injury: challenges and approaches . Toxicol Pathol \n2005 ;33 :1 ‐5 .15805049 \n9 \n\nChalasani \nNP \n, \nHayashi \nPH \n, \nBonkovsky \nHL \n, \nNavarro \nVJ \n, \nLee \nWM \n, \nFontana \nRJ \n. Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug‐induced liver injury . Am J Gastroenterol \n2014 ;109 :950 ‐966 .24935270 \n10 \n\nAlla \nV \n, \nAbraham \nJ \n, \nSiddiqui \nJ \n, \nRaina \nD \n, \nWu \nGY \n, \nChalasani \nNP \n, et al. Autoimmune hepatitis triggered by statins . J Clin Gastroenterol \n2006 ;40 :757 ‐761 .16940892 \n11 \n\nBjornsson \nE \n, \nTalwalkar \nJ \n, \nTreeprasertsuk \nS \n, \nKamath \nPS \n, \nTakahashi \nN \n, \nSanderson \nS \n, et al. Drug‐induced autoimmune hepatitis: clinical characteristics and prognosis . Hepatology \n2010 ;51 :2040 ‐2048 .20512992 \n12 \n\nZignego \nAL \n, \nFerri \nC \n, \nPileri \nSA \n, \nCaini \nP \n, \nBianchi \n\n\nFB \n. Italian Association of the Study of Liver Commission on Extrahepatic Manifestations of HCV infection. Extrahepatic manifestations of hepatitis C virus infection: a general overview and guidelines for a clinical approach . Dig Liver Dis \n2007 ;39 :2 ‐17 .16884964 \n13 \n\nSaadoun \nD \n, \nThibault \nV \n, \nSi Ahmed \nSN \n, \nAlric \nL \n, \nMallet \nM \n, \nGuillaud \nC \n, et al. Sofosbuvir plus ribavirin for hepatitis C virus‐associated cryoglobulinaemia vasculitis: VASCUVALDIC study . Ann Rheum Dis \n2016 ;75 :1777 ‐1782 .26567178 \n14 \n\nRamos‐Casals \nM \n, \nZignego \nAL \n, \nFerri \nC \n, \nBrito‐Zeron \nP \n, \nRetamozo \nS \n, \nCasato \nM \n, et al. International Study Group of Extrahepatic Manifestations related to HCV (ISG‐EHCV). Evidence‐based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection . J Hepatol \n2017 ;66 :1282 ‐1299 .28219772 \n15 \n\nSise \nME \n, \nBloom \nAK \n, \nWisocky \nJ \n, \nLin \nMV \n, \nGustafson \nJL \n, \nLundquist \nAL \n, et al. Treatment of hepatitis C virus‐associated mixed cryoglobulinemia with direct‐acting antiviral agents . Hepatology \n2016 ;63 :408 ‐417 .26474537 \n16 \n\nGragnani \nL \n, \nVisentini \nM \n, \nFognani \nE \n, \nUrraro \nT \n, \nDe Santis \nA \n, \nPetraccia \nL \n, et al. Prospective study of guideline‐tailored therapy with direct‐acting antivirals for hepatitis C virus‐associated mixed cryoglobulinemia . Hepatology \n2016 ;64 :1473 ‐1482 .27483451 \n17 \n\nAnsari \nU \n, \nHenderson \nLI \n, \nStott \nG \n, \nParr \nK \n. Treatment with ledipasvir‐sofosbuvir for hepatitis C resulting in improvement of lichen planus . JAAD Case Rep \n2017 ;3 :67 ‐69 .28229123 \n18 \n\nSugiura \nA \n, \nWada \nS \n, \nMori \nH \n, \nKimura \nT \n, \nMatsuda \nY \n, \nTanaka \nN \n, et al. Successful treatment for chronic hepatitis C‐autoimmune hepatitis overlap syndrome due to daclatasvir and asunaprevir . Case Rep Gastroenterol \n2017 ;11 :305 ‐311 .28626376 \n19 \n\nReig \nM \n, \nMarino \nZ \n, \nPerello \nC \n, \nInarrairaegui \nM \n, \nRibeiro \nA \n, \nLens \nS \n, et al. Unexpected high rate of early tumor recurrence in patients with HCV‐related HCC undergoing interferon‐free therapy . J Hepatol \n2016 ;65 :719 ‐726 .27084592 \n20 \n\nConti \nF \n, \nBuonfiglioli \nF \n, \nScuteri \nA \n, \nCrespi \nC \n, \nBolondi \nL \n, \nCaraceni \nP \n, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV‐related cirrhosis treated with direct‐acting antivirals . J Hepatol \n2016 ;65 :727 ‐733 .27349488 \n21 \n\nTatsumi \nT \n, \nTakehara \nT \n. Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma . Hepatol Res \n2016 ;46 :416 ‐422 .26574168 \n22 \n\nGrandhe \nS \n, \nFrenette \nCT \n. Occurrence and recurrence of hepatocellular carcinoma after successful direct‐acting antiviral therapy for patients with chronic hepatitis C virus infection . Gastroenterol Hepatol (N Y) \n2017 ;13 :421 ‐425 .28867970 \n23 \n\nDebes \nJD \n, \nvan Tilborg \nM \n, \nGroothuismink \nZMA \n, \nHansen \nBE \n, \nSchulze Zur Wiesch \nJ \n, et al. Levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with HCV infection treated with direct‐acting antivirals . Gastroenterology \n2018 ;154 :515 ‐517. e3.29102620 \n24 \n\nOmagari \nK \n, \nKinoshita \nH \n, \nKato \nY \n, \nNakata \nK \n, \nKanematsu \nT \n, \nKusumoto \nY \n, et al. Clinical features of 89 patients with autoimmune hepatitis in Nagasaki Prefecture, Japan . J Gastroenterol \n1999 ;34 :221 ‐226 .10213122 \n25 \n\nLiebman \nHA \n, \nStasi \nR \n. Secondary immune thrombocytopenic purpura . Curr Opin Hematol \n2007 ;14 :557 ‐573 .17934365\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2471-254X",
"issue": "2(10)",
"journal": "Hepatology communications",
"keywords": null,
"medline_ta": "Hepatol Commun",
"mesh_terms": null,
"nlm_unique_id": "101695860",
"other_id": null,
"pages": "1179-1183",
"pmc": null,
"pmid": "30288473",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "27483451;26474537;10580593;28229123;28219772;16940892;10807504;26574168;24799984;28626376;1080096;16884964;11890475;27084592;28867970;24935270;28341748;29102620;26567178;20512992;29545925;17934365;10213122;15805049;27349488",
"title": "Autoimmune Hepatitis During Ledipasvir/Sofosbuvir Treatment of Hepatitis C: A Case Report.",
"title_normalized": "autoimmune hepatitis during ledipasvir sofosbuvir treatment of hepatitis c a case report"
} | [
{
"companynumb": "IT-GILEAD-2018-0367801",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"drugadditional": null,
... |
{
"abstract": "In premenopausal women treated for breast cancer, endocrine therapy combining an aromatase inhibitor (AI) and a gonadotropin-releasing hormone (GnRH) agonist (GA) for ovarian suppression may be indicated in high-risk or in metastatic cancer. AIs are effective in premenopausal women only when ovarian estrogen production is suppressed, a state achievable through the use of GAs. However, a complete suppression sometimes proves elusive. We report here three cases of ovarian suppression failure in premenopausal breast cancer patients who received adjuvant AI+GA. Frequency of GA administration, BMI, and young age could affect gonadotropin suppression and may be implied in these failures. Clinical monitoring of these patients is advisable, and hormone assays and pelvic ultrasound should be performed in case of symptoms of estrogen activity.",
"affiliations": "Université Claude Bernard, Domaine Rockefeller, 8 avenue Rockefeller, 69373 Lyon Cedex 8, France.;Département de Chirurgie, Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.;Département de Cancérologie Médicale, Centre Léon-Bérard, 28 rue Laënnec, 69008 Lyon, France.;Département de Cancérologie Médicale, Centre Léon-Bérard, 28 rue Laënnec, 69008 Lyon, France.;Département de Chirurgie, Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France; Service de Gynécologie, Centre Hospitalier Lyon Sud, 165 chemin du grand Revoyet, 69130 Pierre-Bénite, France. Electronic address: christine.rousset-jablonski@lyon.unicancer.fr.",
"authors": "de Ciantis|M|M|;Faure|C|C|;Heudel|P-E|PE|;Tredan|O|O|;Rousset-Jablonski|C|C|",
"chemical_list": "D047072:Aromatase Inhibitors; D007987:Gonadotropin-Releasing Hormone",
"country": "France",
"delete": false,
"doi": "10.1016/j.jogoh.2018.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-7847",
"issue": "47(6)",
"journal": "Journal of gynecology obstetrics and human reproduction",
"keywords": "Breast cancer; Endocrine therapy; Estradiol; GnRH agonist; Ovarian suppression; Premenopausal",
"medline_ta": "J Gynecol Obstet Hum Reprod",
"mesh_terms": "D000328:Adult; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D004359:Drug Therapy, Combination; D005260:Female; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D010053:Ovary",
"nlm_unique_id": "101701588",
"other_id": null,
"pages": "261-264",
"pmc": null,
"pmid": "29510273",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ovarian suppression failure during GnRH agonist treatment: A report of three breast cancer patients.",
"title_normalized": "ovarian suppression failure during gnrh agonist treatment a report of three breast cancer patients"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1007542",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
... |
{
"abstract": "Maternal drug abuse may influence neonatal outcomes. We compared neonatal outcomes of patients with urine screened positive for commonly abused drugs (CAD) versus those who were screened negative, and reviewed the pattern of drugs detected at a university teaching hospital.\n\n\n\nUrine samples collected from babies with suspected illicit drug exposure who were admitted to the neonatal unit were sent for comprehensive drug screen (CDS) performed by liquid chromatographytime- of-flight mass spectrometry (LC-TOF/MS). The screening library can detect more than 300 drugs and their metabolites. Fluorescence polarization immunoassay (FPIA) was also used to screen for cannabinoids which were not detected by the present LC-TOF/MS method. Symptoms suggestive of drug exposure and history of maternal substance misuse were recorded.\n\n\n\nCommonly abused drugs (CAD) including methadone, morphine, codeine, methamphetamine, ketamine, midazolam and heroin were present in the urine specimens of 46 (24.2%) of 190 neonates. Eighty-one (42.6%) urine samples screened positive for other drugs, which include antibiotics, lidocaine and pethidine administered during delivery. Drugs were undetectable in 33.2% samples. Urine positive for CAD was independently associated with maternal history of substance misuse (0.0001), birth-weight 2.5 kg (OR 2.9,0.01), neonatal withdrawal symptomatology (OR=8.89, 0.0001); but not with risk of preterm delivery. Logistic regression demonstrated that neonates with maternal history of substance misuse and CAD positivity were 5.99 (p=0.021) and 5.91 (0.0005) times more likely to have withdrawal symptoms.\n\n\n\nCADs are isolated in the CDS of nearly one-fourth of neonates. Neonates with maternal history of CAD exposure as evidenced by positive urine CDS are associated with low birth weight, and symptoms of drug withdrawal.",
"affiliations": "Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.",
"authors": "Hon|Kam L|KL|;Chan|Michael H M|MH|;Ng|Ming H J|MH|;Ho|Chi C|CC|;Tsang|Kathy Y C|KY|;Tam|Wing H|WH|;Ho|Chung S|CS|",
"chemical_list": "D013287:Illicit Drugs",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574884711666161010164435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8847",
"issue": "11(4)",
"journal": "Current clinical pharmacology",
"keywords": null,
"medline_ta": "Curr Clin Pharmacol",
"mesh_terms": "D016022:Case-Control Studies; D002853:Chromatography, Liquid; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D013287:Illicit Drugs; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D016015:Logistic Models; D013058:Mass Spectrometry; D009357:Neonatal Abstinence Syndrome; D011247:Pregnancy; D011248:Pregnancy Complications; D012189:Retrospective Studies; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "101273158",
"other_id": null,
"pages": "274-281",
"pmc": null,
"pmid": "27748174",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Urine Comprehensive Drug Screen, Low Birth Weight and Withdrawal Symptoms in a Neonatal Unit: A Case Control Study.",
"title_normalized": "urine comprehensive drug screen low birth weight and withdrawal symptoms in a neonatal unit a case control study"
} | [
{
"companynumb": "HK-JNJFOC-20170113058",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Drug-induced immune thrombocytopenia (DITP) is a challenging clinical problem that is under-recognized, difficult to diagnose and associated with severe bleeding complications. DITP may be caused by classic drug-dependent platelet antibodies (eg, quinine); haptens (eg, penicillin); fiban-dependent antibodies (eg, tirofiban); monoclonal antibodies (eg, abciximab); autoantibody formation (eg, gold); and immune complex formation (eg, heparin). A thorough clinical history is essential in establishing the diagnosis of DITP and should include exposures to prescription medications, herbal preparations and even certain foods and beverages. Clinical and laboratory criteria have been established to determine the likelihood of a drug being the cause of thrombocytopenia, but these criteria can only be applied retrospectively. The most commonly implicated drugs include quinine, quinidine, trimethoprim/sulfamethoxazole and vancomycin. We propose a practical approach to the diagnosis of the patient with suspected DITP. Key features are: the presence of severe thrombocytopenia (platelet nadir <20×10(9)/L); bleeding complications; onset 5 to 10days after first drug exposure, or within hours of subsequent exposures or after first exposure to fibans or abciximab; and exposure to drugs that have been previously implicated in DITP reactions. Treatment involves stopping the drug(s), administering platelet transfusions or other therapies if bleeding is present and counselling on future drug avoidance. The diagnosis can be confirmed by a positive drug re-challenge, which is often impractical, or by demonstrating drug-dependent platelet reactive antibodies in vitro. Current test methods, which are mostly flow cytometry-based, must show drug-dependence, immunoglobulin binding, platelet specificity and ideally should be reproducible across laboratories. Improved standardization and accessibility of laboratory testing should be a focus of future research.",
"affiliations": "Michael G. DeGroote School of Medicine, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. arnold@mcmaster.ca",
"authors": "Arnold|Donald M|DM|;Nazi|Ishac|I|;Warkentin|Theodore E|TE|;Smith|James W|JW|;Toltl|Lisa J|LJ|;George|James N|JN|;Kelton|John G|JG|",
"chemical_list": "D000906:Antibodies; D000911:Antibodies, Monoclonal; D014640:Vancomycin; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-7963",
"issue": "27(3)",
"journal": "Transfusion medicine reviews",
"keywords": null,
"medline_ta": "Transfus Med Rev",
"mesh_terms": "D000368:Aged; D000906:Antibodies; D000911:Antibodies, Monoclonal; D001792:Blood Platelets; D004696:Endocarditis; D005260:Female; D006350:Heart Valve Prosthesis; D006493:Heparin; D006801:Humans; D008943:Mitral Valve; D010976:Platelet Count; D017713:Platelet Transfusion; D015203:Reproducibility of Results; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "8709027",
"other_id": "CAMS3209",
"pages": "137-45",
"pmc": null,
"pmid": "23845922",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "16266914;10730685;12121967;20008194;20502168;14102898;1883209;23422751;5814581;15277669;11126885;17124091;23325832;15706031;17329695;17665503;11803505;5925984;22364760;16965386;20500502;9867731;11389025;20110436;14316534;21487107;17687133;17329697;8241614;12200368;13313580;23121994;19344362;12956768;20525061;15609288;23384227;8599173;19260124;15081439;10363983;14744847;21960587;7949124;20406019;19429867;8982052;21899392;17200219;5798625;12210813;15140135;7195922;16099887;6805076;4856606;19197137;11877279;868869;8121459;6485079;580789;20530792",
"title": "Approach to the diagnosis and management of drug-induced immune thrombocytopenia.",
"title_normalized": "approach to the diagnosis and management of drug induced immune thrombocytopenia"
} | [
{
"companynumb": "CA-ROXANE LABORATORIES, INC.-2014-BI-35182GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditi... |
{
"abstract": "Zolpidem is an imidazopyridine nonbenzodiazepine hypnotic drug with a high affinity to the α1 subunit of the gamma amino butyric acid A receptor It is the first pharmacological option in the short-term management of sleep-onset insomnia. Initially considered a safer drug compared to benzodiazepines because of lower liability for abuse and dependence, recently, an increasing body of reports has questioned zolpidem's proneness to misuse. In this report, we describe a case of serious zolpidem abuse requiring pharmacological washout during hospitalization because of previous withdrawal seizures in a patient with chronic sleep-onset and maintenance insomnia.",
"affiliations": "Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;Community Psychiatry Service OSC-EOC, Lugano, Switzerland.;Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.",
"authors": "Chiaro|Giacomo|G|;Castelnovo|Anna|A|;Bianco|Giovanni|G|;Maffei|Piermario|P|;Manconi|Mauro|M|",
"chemical_list": "D000927:Anticonvulsants; D017367:Serotonin Uptake Inhibitors; D000068776:Sleep Aids, Pharmaceutical; D000077287:Levetiracetam; D000069583:Pregabalin; D002998:Clonazepam; D000077334:Zolpidem; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "14(7)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "abuse; actigraphy; electroencephalography; insomnia; power spectrum; video polysomnography; zolpidem",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D002908:Chronic Disease; D002998:Clonazepam; D005260:Female; D006760:Hospitalization; D006801:Humans; D000077287:Levetiracetam; D000069583:Pregabalin; D012640:Seizures; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D000068776:Sleep Aids, Pharmaceutical; D007319:Sleep Initiation and Maintenance Disorders; D019966:Substance-Related Disorders; D000077334:Zolpidem",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "1257-1259",
"pmc": null,
"pmid": "29991431",
"pubdate": "2018-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17362446;9610942;14519173;14756709;18068286;23093474;22489594;24520235;20218806;22036737;21448102;21407000;18612891;25455931;28993837;17882616;17875189;18289154;1881993;21037147;24497662;25984284;28659704;18085123;25763219;10576495;12680751;24467433",
"title": "Severe Chronic Abuse of Zolpidem in Refractory Insomnia.",
"title_normalized": "severe chronic abuse of zolpidem in refractory insomnia"
} | [
{
"companynumb": "PHHY2018CH066225",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditional": null... |
{
"abstract": "Cutaneous adverse drug reactions produce a significant clinical, financial, and psychological burden on our healthcare industry. The importance of considering a drug reaction in the cause of any dermatitis is underscored by the diversity of clinical manifestations and the prolific rate of drug discovery and approval. We present an update on the variety of drug reactions encountered in the inpatient and outpatient setting. Immunomodulatory drugs used in oncology will be reviewed separately as their clinical manifestations cross many reaction patters and morphologies.",
"affiliations": "Division of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky, USA. Electronic address: rtspau01@icloud.com.;Division of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky, USA.;Division of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky, USA.",
"authors": "Spaulding|Robert T|RT|;Owen|Cindy E|CE|;Callen|Jeffrey P|JP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clindermatol.2020.10.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0738-081X",
"issue": "39(2)",
"journal": "Clinics in dermatology",
"keywords": null,
"medline_ta": "Clin Dermatol",
"mesh_terms": "D003875:Drug Eruptions; D064420:Drug-Related Side Effects and Adverse Reactions; D005076:Exanthema; D006801:Humans; D012867:Skin",
"nlm_unique_id": "8406412",
"other_id": null,
"pages": "233-239",
"pmc": null,
"pmid": "34272016",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "New patterns of cutaneous drug eruptions.",
"title_normalized": "new patterns of cutaneous drug eruptions"
} | [
{
"companynumb": "NVSC2020US340776",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nPerinatal group A streptococcal infection is a rare but life-threatening condition. Few reports have focused on its clinical characteristics and how to prevent deterioration. We report our experience with two antenatal fatal cases and reviewed 96 cases in the literature to assess the clinical characteristics of group A streptococcal infection.\n\n\nMETHODS\nEnglish-language clinical reports of antenatal and postnatal group A streptococcal infection in 1974-2019 were retrieved and examined. Relationships between clinical characteristics and maternal outcomes were assessed.\n\n\nRESULTS\nUnivariate analysis revealed that antenatal group A streptococcal infection was significantly associated with an age of ≤19 or ≥ 35 years, cesarean section, sore throat as an initial symptom, positive throat culture, maternal death and fetal death. Multivariate analysis revealed that antenatal onset (odds ratio = 7.922, 95% confidence interval = 1.297-48.374; P = 0.025) and a quick sepsis-related organ-failure assessment score (qSOFA; low blood pressure, high respiratory rate or altered mental status) of ≥2 (odds ratio = 6.166, 95% confidence interval = 1.066-35.670; P = 0.042) were significantly related to maternal death.\n\n\nCONCLUSIONS\nPer our findings, antenatal group A streptococcal infection was significantly associated with maternal and fetal death. Further, the antenatal infection was revealed as a more critical risk factor. We suggest that the presence of any sign related to the qSOFA is a potential clue suspecting perinatal group A streptococcal infection in primary obstetric facilities.",
"affiliations": "Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan.",
"authors": "Arai|Tomohiro|T|https://orcid.org/0000-0002-8326-7864;Takai|Yasushi|Y|;Samejima|Kouki|K|;Matsunaga|Shigetaka|S|;Ono|Yoshihisa|Y|;Seki|Hiroyuki|H|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14497",
"fulltext": "\n==== Front\nJ Obstet Gynaecol Res\nJ Obstet Gynaecol Res\n10.1111/(ISSN)1447-0756\nJOG\nThe Journal of Obstetrics and Gynaecology Research\n1341-8076 1447-0756 John Wiley & Sons Australia, Ltd Kyoto, Japan \n\n32945073\n10.1111/jog.14497\nJOG14497\nOriginal Article\nOriginal Articles\nHow could we suspect life‐threatening perinatal group A streptococcal infection?\nPerinatal streptococcal infectionT. Arai et al.Arai Tomohiro https://orcid.org/0000-0002-8326-7864\n1\ntomo8745@gmail.com Takai Yasushi \n1\n Samejima Kouki \n1\n Matsunaga Shigetaka \n1\n Ono Yoshihisa \n1\n Seki Hiroyuki \n1\n \n1 \nCenter for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center\nSaitama Medical University\nSaitama\nJapan\n\n* \nCorrespondence: Dr. Tomohiro Arai, Center for Maternal, Fetal, and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350‐8550, Japan, Email: tomo8745@gmail.com\n\n17 9 2020 \n12 2020 \n46 12 10.1111/jog.v46.122573 2581\n22 4 2020 22 8 2020 05 9 2020 © 2020 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAim\nPerinatal group A streptococcal infection is a rare but life‐threatening condition. Few reports have focused on its clinical characteristics and how to prevent deterioration. We report our experience with two antenatal fatal cases and reviewed 96 cases in the literature to assess the clinical characteristics of group A streptococcal infection.\n\nMethods\nEnglish‐language clinical reports of antenatal and postnatal group A streptococcal infection in 1974–2019 were retrieved and examined. Relationships between clinical characteristics and maternal outcomes were assessed.\n\nResults\nUnivariate analysis revealed that antenatal group A streptococcal infection was significantly associated with an age of ≤19 or ≥ 35 years, cesarean section, sore throat as an initial symptom, positive throat culture, maternal death and fetal death. Multivariate analysis revealed that antenatal onset (odds ratio = 7.922, 95% confidence interval = 1.297–48.374; P = 0.025) and a quick sepsis‐related organ‐failure assessment score (qSOFA; low blood pressure, high respiratory rate or altered mental status) of ≥2 (odds ratio = 6.166, 95% confidence interval = 1.066–35.670; P = 0.042) were significantly related to maternal death.\n\nConclusion\nPer our findings, antenatal group A streptococcal infection was significantly associated with maternal and fetal death. Further, the antenatal infection was revealed as a more critical risk factor. We suggest that the presence of any sign related to the qSOFA is a potential clue suspecting perinatal group A streptococcal infection in primary obstetric facilities.\n\ngroup A streptococcal infectionmaternal sepsisperinatal mortality source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:23.12.2020\n==== Body\nIntroduction\nPerinatal group A streptococcal (GAS) infection is a rare disease, occurring in six of every 100 000 births according to a North American report.\n1\n The largest case study worldwide included only 67 cases.\n2\n Even in the current age, in which hygienic conditions, antibiotics and intensive care settings have undergone significant advances, perinatal GAS infections can induce sudden septic shock (toxic shock syndrome\n3\n), resulting in the death of the mother and/or infants. Due to the rarity of the condition, detailed pathophysiology and its clinical characteristics have not been understood. Characteristics of vulnerable pregnant women, that is, important information for clinician, have also been unknown. We report two fatal cases, possibly due to GAS infection and analyzed the clinical features of perinatal GAS infection by reviewing the literature.\n\nCase Reports\nCase 1\n\nPatient: A 26‐year‐old woman.\n\n\nPast obstetric history: Gravida 2, para 1. Three years prior, the patient was transported to our hospital due to the rupture of membranes and labor with no prenatal care. An emergency cesarean section due to breech presentation was performed and a 2214 g healthy male was delivered.\n\n\nPast medical history: Nothing remarkable.\n\n\nHistory of present illness: At 13 weeks' gestation, the patient presented to a clinic with abdominal pain. She was diagnosed with a potential threat of miscarriage because of vaginal bleeding. Despite the offer of hospitalization, she refused and returned home. Six hours later, she experienced a rupture of the membranes and spontaneous abortion at home and thus returned to the clinic. The transvaginal ultrasound revealed a retained placenta; she decided to be admitted and undergo surgical treatment. However, she experienced sudden shortness of breath on admission, followed by altered mental status. Since her systolic blood pressure dropped to 60 mmHg, and peripheral capillary oxygen saturation (SpO2) also dropped to 60%, she was provided artificial ventilation. Despite the initial treatment, she went into cardiopulmonary arrest. She was transported to our tertiary medical center while being resuscitated. On arrival, she was still under cardiopulmonary arrest, and the resuscitation was continued. Her laboratory findings showed the following: white blood cell (WBC) count, 35 600 cells/μL; hemoglobin, 9.0 g/dL; platelet count, 113 000 cells/μL; D‐dimer, 32.0 μg/mL; fibrinogen, <70 mg/dL; blood urea nitrogen, 26.0 mg/dL; creatinine, 1.62 mg/dL; aspartate aminotransferase, 3993 U/L; alanine aminotransferase, 3041 U/L; C‐reactive protein, 8.4 mg/dL and procalcitonin, 9.5 ng/mL. GAS was later detected from a culture of a vaginal sample taken at this time. Transthoracic echocardiography revealed no right ventricular dilatation or pericardial effusion. Because she did not respond to resuscitation, percutaneous cardiopulmonary support was started. An enhanced computed tomography scan revealed no pulmonary embolism but diffuse infiltration in the lungs. She died 11 h and 36 min after the initial examination at the clinic.\n\nCase 2\n\nPatient: A 37‐year‐old woman.\n\n\nPast obstetric history: Gravida 1, para 0.\n\n\nPast medical history: Acute hepatitis at 24 years of age.\n\n\nHistory of present illness: The patient had regular prenatal check‐ups at a clinic. At 21 weeks' gestation, she presented with a fever of 38.0°C. Because she was suspected of having an influenza viral infection, she was prescribed oseltamivir and went home. Hypogastric pain appeared, and she returned to the clinic 6 h later. Upon arrival, her body temperature was 39°C, blood pressure was 91/62 mmHg and heart rate was 107 beats per minute. Intrauterine fetal death was diagnosed with transabdominal ultrasound. As the influenza point‐of‐care test result was negative and her WBC count elevated to 13 600/μL, intravenous flomoxef was initiated. Labor started after that, and she had a spontaneous abortion. The placenta was delivered simultaneously, revealing bloody amniotic fluid. Directly after the delivery, significant bleeding was noted, and the patient appeared to be drowsy. At this time, her blood pressure was 83/56 mmHg, heart rate was 124 beats per minute and postnatal hemorrhage had reached 1272 g. Therefore, she was transferred to a secondary medical center. Laboratory findings on arrival showed the following: WBC count, 32 800 cells/μL; hemoglobin, 8.1 g/dL; platelet count, 67 000 cells/μL; D‐dimer, 907.3 μg/mL; fibrinogen, <25 mg/dL; blood urea nitrogen, 31.0 mg/dL; creatinine, 2.28 mg/dL; aspartate aminotransferase, 146 U/L; alanine aminotransferase, 22 U/L and C‐reactive protein, 9.3 mg/dL. GAS was later identified from vaginal discharge taken at this hospital. She went into cardiopulmonary arrest, and cardiopulmonary resuscitation was provided. She restored spontaneous circulation 2 min later and was transferred to our tertiary medical center. She again went into cardiopulmonary arrest during the transfer. After arrival, she did not respond to continued attempts of cardiopulmonary resuscitation. She died 21 h and 46 min after the initial visit to the clinic.\n\nOur two cases suspected of perinatal GAS infection had severe maternal outcomes with an astonishingly acute clinical course. Several studies have addressed the clinical characteristics of perinatal GAS infection. Of these, Hamilton et al. reported the largest number of cases (67 patients, including 10 antenatal) from the literature review.\n2\n However, limited evidence is available on the clinical features indicative of perinatal GAS infection and, particularly, which patients require heightened attention. On the basis of the severe outcome of our cases, we hypothesized that antenatal GAS infection was associated with the outcome. To test this hypothesis, we compared the clinical characteristics of GAS infection between antenatal and postnatal onsets. We then assessed the clinical characteristics that affected the maternal outcome.\n\nMaterials and Methods\nData extraction\nEnglish‐language clinical reports describing antenatal and postnatal GAS infection between 1974 and 2019 were examined according to a PubMed database search using 'pregnancy' and 'group A streptococcus' as search terms.\n\nBecause data were incomplete in some of the published reports, we used the following definitions: Data were defined as a valid 'negative' finding when at least one finding, whether positive or negative, was reported for another item in the same category. Conversely, data were defined as 'missing' when no findings were reported for the category as a whole. For example, if abdominal pain was not reported as an initial symptom in a clinical report, abdominal pain was defined as 'negative' if at least one other initial symptom was reported, while abdominal pain was defined as 'missing' if no initial symptoms were reported. Missing data were not included in the analysis. Among the data collected, quick sepsis‐related organ failure assessment (qSOFA) score\n4\n and CENTOR score (Cough absent, Exudate, Nodes, Temperature, young OR old modifier: a widely used diagnostic score for GAS pharyngitis)\n5\n were dependent variables, whereas the other variables were independent variables. Cases in which vasopressor information was given were defined as 'systolic pressure <90 mmHg'. In the absence of actual numerical values, these terms were defined as follows: fever, body temperature ≥ 37.5°C; hypotension, systolic pressure < 90 mmHg; tachycardia, heart rate ≥ 100 beats per minute; tachypnea, respiratory rate > 20 breaths per minute; shock, systolic pressure < 90 mmHg and heart rate ≥ 100 beats per minute. Therefore, only the definition of the term 'fever' itself was not clearly achieved either as ≥38.0°C or ≥ 39.0°C. Cases in which the indicated clinical feature was not reported (i.e. missing) were not included in subsequent calculations.\n\nStatistical analysis\nThe above data were analyzed with IBM SPSS Statistics for Windows, version 23.0 (IBM Corp.). The following tests were used for comparison: Shapiro‐Wilks test for the distribution of variables, Student t‐test for normally distributed variables, Mann–Whitney U test for non‐normally distributed variables; two‐tailed Pearson's chi‐square test and one‐tailed Fisher's exact test for categorical variables; multivariate logistic regression analysis for regression analysis. The level of significance adopted was 5% (α = 0.05).\n\nEthical approval\nThis study was approved by the ethical board at Saitama Medical Center (registration number: 2233).\n\nResults\nWe included a total of 98 patients reported over a long time period (45 years) (Table 1\n\n6\n, \n7\n, \n8\n, \n9\n, \n10\n, \n11\n, \n12\n, \n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n, \n19\n, \n20\n, \n21\n, \n22\n, \n23\n, \n24\n, \n25\n, \n26\n, \n27\n, \n28\n, \n29\n, \n30\n, \n31\n, \n32\n, \n33\n, \n34\n, \n35\n, \n36\n, \n37\n, \n38\n, \n39\n, \n40\n, \n41\n, \n42\n, \n43\n, \n44\n, \n45\n, \n46\n, \n47\n, \n48\n, \n49\n, \n50\n, \n51\n, \n52\n, \n53\n, \n54\n, \n55\n, \n56\n, \n57\n, \n58\n, \n59\n, \n60\n, \n61\n). Patient characteristics were compared between antenatal and postnatal GAS infection groups (Table 2). Of the 98 patients included, 25 were antenatal and 73 were postnatal infections. On univariate analysis, the antenatal GAS infection had a significant association with an age of ≤19 or ≥ 35 years, cesarean section, sore throat as an initial symptom, positive throat culture, maternal death and fetal death. In contrast, the postnatal GAS infection had a significant association with onset during hospitalization, abnormal vaginal discharge and any surgical interventions.\n\nTable 1 Clinical cases of GAS infection reviewed in this study\n\nAge\tOnset of symptoms\tMode of delivery\tMaternal outcome\tFetal outcome\tReference\tPublication year\t\nAntenatal onset (n = 25)\t\nTime of onset unknown (n = 1)\t\n22\tNG\tVaginal delivery\tSurvived\tDied\t[6]\t1993\t\nTime of onset 1st trimester (n = 3)\t\n40\tGW 7\tVaginal delivery\tSurvived\tNG\t[7]\t1991\t\n40\tGW 10\tVaginal delivery\tDied\tDied\t[8]\t2015\t\n\n26\n\t\nGW 13\n\t\nVaginal delivery\n\t\nDied\n\t\nDied\n\t\nCase 1\n\t\n2020\n\t\nTime of onset 2nd trimester (n = 5)\t\n32\tGW 15\tVaginal delivery\tDied\tDied\t[8]\t2015\t\n35\tGW 18\tNG\tDied\tDied\t[8]\t2015\t\n\n37\n\t\nGW 21\n\t\nVaginal delivery\n\t\nDied\n\t\nDied\n\t\nCase 2\n\t\n2020\n\t\n21\tGW 27\tNG\tSurvived\tNG\t[9]\t1996\t\n19\tGW 27\tVaginal delivery\tSurvived\tSurvived\t[10]\t2013\t\nTime of onset 3rd trimester (n = 16)\t\n37\tGW 28\tCesarean section\tDied\tNG\t[11]\t2001\t\n24\tGW 32\tCesarean section\tSurvived\tSurvived\t[12]\t2016\t\nNG\tGW 34\tCesarean section\tSurvived\tSurvived\t[13]\t1990\t\n43\tGW 34\tCesarean section\tDied\tDied\t[14]\t1996\t\n29\tGW 34\tVaginal delivery\tDied\tDied\t[15]\t1997\t\n42\tGW 34\tCesarean section\tDied\tDied\t[15]\t1997\t\n31\tGW 34\tCesarean section\tSurvived\tSurvived\t[16]\t2001\t\n38\tGW 34\tVaginal delivery\tDied\tDied\t\n8\n\t2015\t\n35\tGW 34\tVaginal delivery\tSurvived\tSurvived\t[17]\t2017\t\n36\tGW 35\tNG\tDied\tDied\t\n8\n\t2015\t\n32\tGW 36\tCesarean section\tDied\tDied\t[18]\t1995\t\n36\tGW 36\tVaginal delivery\tDied\tDied\t[19]\t2001\t\n36\tGW 36\tVaginal delivery\tSurvived\tNG\t[20]\t2007\t\n16\tGW 37\tVaginal delivery\tDied\tDied\t[21]\t2010\t\n35\tGW 37\tNG\tDied\tSurvived\t[22]\t2015\t\nNG\tGW 40\tVaginal delivery\tSurvived\tSurvived\t[13]\t1990\t\nPostpartum onset (n = 73)\t\nTime of onset unknown (n = 12)\t\n29\tNG\tNG\tDied\tNG\t[23]\t1989\t\n34\tNG\tNG\tSurvived\tNG\t[23]\t1989\t\n29\tNG\tCesarean section\tSurvived\tNG\t[24]\t2004\t\nNG\tNG\tVaginal delivery\tSurvived\tSurvived\t[25]\t2005\t\nNG\tNG\tVaginal delivery\tSurvived\tSurvived\t[25]\t2005\t\nNG\tNG\tVaginal delivery\tSurvived\tSurvived\t[25]\t2005\t\nNG\tNG\tVaginal delivery\tSurvived\tSurvived\t[25]\t2005\t\nNG\tNG\tVaginal delivery\tSurvived\tSurvived\t[25]\t2005\t\n25\tNG\tNG\tSurvived\tNG\t[26]\t2008\t\n36\tNG\tNG\tSurvived\tNG\t[26]\t2008\t\n25\tNG\tNG\tSurvived\tNG\t[26]\t2008\t\n19\tNG\tNG\tSurvived\tNG\t[26]\t2008\t\nTime of onset 0–24 h (n = 21)\t\nNG\tImmediately\tVaginal delivery\tSurvived\tSurvived\t[13]\t1990\t\n31\tImmediately\tVaginal delivery\tSurvived\tSurvived\t[27]\t1993\t\n32\tImmediately\tVaginal delivery\tSurvived\tSurvived\t[30]\t2018\t\n19\t25 min\tCesarean section\tDied\tSurvived\t[29]\t1974\t\n20\t1 h\tVaginal delivery\tDied\tSurvived\t\n6\n\t1994\t\n33\tA few hours\tVaginal delivery\tSurvived\tNG\t[22]\t2017\t\n27\t8 h\tVaginal delivery\tSurvived\tSurvived\t[30]\t2008\t\n24\t12 h\tVaginal delivery\tSurvived\tSurvived\t[31]\t2005\t\n27\t12 h\tVaginal delivery\tSurvived\tSurvived\t[32]\t2011\t\n32\t16 h\tCesarean section\tSurvived\tSurvived\t[19]\t2001\t\n33\t18 h\tVaginal delivery\tSurvived\tSurvived\t[19]\t2001\t\n28\t20 h\tVaginal delivery\tDied\tSurvived\t[33]\t1993\t\n25\t20 h\tVaginal delivery\tSurvived\tDied\t[27]\t1993\t\n21\t24 h\tVaginal delivery\tDied\tSurvived\t[34]\t1996\t\n17\t24 h\tVaginal delivery\tSurvived\tSurvived\t[35]\t1999\t\n22\t24 h\tVaginal delivery\tSurvived\tNG\t[19]\t2001\t\nNG\t24 h\tVaginal delivery\tSurvived\tSurvived\t[36]\t2001\t\n26\t24 h\tNG\tSurvived\tNG\t[26]\t2008\t\n34\t24 h\tCesarean section\tDied\tSurvived\t[37]\t2008\t\n26\t24 h\tNG\tDied\tSurvived\t\n8\n\t2015\t\n28\t24 h\tVaginal delivery\tSurvived\tNG\t[38]\t2017\t\nTime of onset 1–2 days (n = 14)\t\n28\t29 h\tVaginal delivery\tSurvived\tSurvived\t[39]\t2008\t\n39\t30 h\tVaginal delivery\tDied\tSurvived\t[40]\t2013\t\n34\t36 h\tVaginal delivery\tSurvived\tNG\t[22]\t2017\t\n27\t2 days\tVaginal delivery\tSurvived\tSurvived\t[41]\t1992\t\n36\t2 days\tVaginal delivery\tSurvived\tSurvived\t[42]\t1995\t\n29\t2 days\tVaginal delivery\tSurvived\tSurvived\t[43]\t1996\t\n26\t2 days\tVaginal delivery\tSurvived\tSurvived\t[44]\t2003\t\n29\t2 days\tVaginal delivery\tSurvived\tNG\t[45]\t2005\t\n31\t2 days\tVaginal delivery\tSurvived\tSurvived\t[46]\t2005\t\n35\t2 days\tCesarean section\tSurvived\tSurvived\t[47]\t2009\t\n24\t2 days\tVaginal delivery\tSurvived\tNG\t[10]\t2013\t\n27\t2 days\tVaginal delivery\tSurvived\tNG\t[10]\t2013\t\n31\t2 days\tVaginal delivery\tSurvived\tNG\t[48]\t2013\t\n28\t2 days\tVaginal delivery\tSurvived\tNG\t[38]\t2017\t\nTime of onset 3–4 days (n = 14)\t\n36\t3 days\tVaginal delivery\tSurvived\tSurvived\t[49]\t1993\t\nNG\t3 days\tVaginal delivery\tSurvived\tSurvived\t[50]\t2002\t\nNG\t3 days\tVaginal delivery\tDied\tSurvived\t[50]\t2002\t\n22\t3 days\tVaginal delivery\tSurvived\tNG\t[51]\t2009\t\n29\t3 days\tCesarean section\tDied\tSurvived\t[40]\t2013\t\n22\t3 days\tVaginal delivery\tSurvived\tNG\t[38]\t2017\t\n37\t3 days\tVaginal delivery\tSurvived\tNG\t[22]\t2017\t\n25\t4 days\tVaginal delivery\tSurvived\tSurvived\t[52]\t1991\t\n14\t4 days\tVaginal delivery\tSurvived\tSurvived\t[53]\t1993\t\n27\t4 days\tVaginal delivery\tDied\tNG\t\n9\n\t1996\t\n30\t4 days\tVaginal delivery\tSurvived\tNG\t[54]\t2001\t\nNG\t4 days\tVaginal delivery\tSurvived\tSurvived\t[36]\t2001\t\n29\t4 days\tNG\tSurvived\tNG\t[26]\t2008\t\n37\t4 days\tVaginal delivery\tSurvived\tSurvived\t[55]\t2015\t\nTime of onset 5–7 days (n = 6)\t\n39\t5 days\tVaginal delivery\tSurvived\tSurvived\t[56]\t2001\t\n30\t5 days\tVaginal delivery\tSurvived\tNG\t[57]\t2008\t\n35\t5 days\tVaginal delivery\tDied\tNG\t[22]\t2017\t\n37\t6 days\tVaginal delivery\tSurvived\tNG\t\n9\n\t1996\t\n22\t7 days\tVaginal delivery\tSurvived\tSurvived\t[41]\t1992\t\n27\t7 days\tVaginal delivery\tSurvived\tNG\t[10]\t2013\t\nTime of onset ≥8 days (n = 6)\t\n20\t8 days\tVaginal delivery\tSurvived\tNG\t[19]\t2001\t\n26\t13 days\tCesarean section\tSurvived\tNG\t[58]\t2003\t\n23\t14 days\tVaginal delivery\tSurvived\tSurvived\t[59]\t1990\t\n36\t22 days\tNG\tSurvived\tNG\t[26]\t2008\t\n23\t3 weeks\tCesarean section\tSurvived\tSurvived\t[60]\t1984\t\n27\t5 weeks\tVaginal delivery\tSurvived\tSurvived\t[61]\t2005\t\nBold characters indicate cases that we experienced.\n\nGAS, group A streptococcal; GW, gestational weeks; NG, not given.\n\nTable 2 Clinical characteristics of perinatal GAS infection\n\nCharacteristics of GAS infection\tNo. (%) of patients with the indicated feature\n†\n\n,\n\n‡\n\n\t\nP‐value\t\nAntenatal\tPostnatal\t\n(n = 25)\t(n = 73)\t\nAge, ≤19 or ≥35 years\t15 / 23 (65.2)\t15 / 63 (23.8)\t0.000\n*\n\n\t\nMultiparous\t13 / 17 (76.5)\t35 / 45 (77.8)\t0.580\t\nOnset during hospitalization\t1 / 25 (4.0)\t26 / 65 (40.0)\t0.001\n*\n\n\t\nMode of delivery\t\t\t\t\nVaginal delivery\t13 / 20 (65.0)\t54 / 62 (87.1)\t0.034\n**\n\n\t\nCesarean section\t7 / 20 (35.0)\t8 / 62 (12.9)\t\t\nInitial symptoms\t\t\t\t\nFever, chills, full‐like symptoms\t16 / 24 (66.7)\t45 / 60 (75.0)\t0.439\t\nSore throat with or without other upper respiratory symptoms\t7 / 24 (29.2)\t5 / 60 (8.3)\t0.020\n**\n\n\t\nNausea, vomiting, diarrhea\t6 / 24 (25.0)\t8 / 60 (13.3)\t0.165\t\nAbdominal pain\t8 / 24 (33.3)\t34 / 60 (56.7)\t0.053\t\nClinical features\t\t\t\t\nFever (≥38.0°C)\t11 / 19 (57.9)\t26 / 57 (45.6)\t0.354\t\nHypotension (systolic pressure ≤ 90 mmHg)\t10 / 19 (52.6)\t26 / 57 (45.6)\t0.596\t\nTachycardia (≥100 beats per min)\t11 / 19 (57.9)\t31 / 57 (54.4)\t0.790\t\nLeukocytosis (WBC count >11 000/mm3)\t4 / 19 (21.1)\t20 / 57 (35.1)\t0.254\t\nUterine tenderness\t3 / 19 (15.8)\t17 / 57 (29.8)\t0.229\t\nAbnormal vaginal discharge\t2 / 19 (10.5)\t20 / 57 (35.1)\t0.041\n*\n\n\t\nErythema\t3 / 19 (15.8)\t15 / 57 (26.3)\t0.273\t\nExtremity pain\t2 / 19 (10.5)\t13 / 57 (22.8)\t0.207\t\nSore throat+CENTOR, ≥2\t4 / 11 (36.4)\t4 / 6 (66.7)\t0.247\t\nqSOFA score, ≥2\t6 / 15 (40.0)\t15 / 59 (25.4)\t0.210\t\nPharmacological interventions\t\t\t\t\nAntibiotic treatment\t19 / 21 (90.5)\t67 /68 (98.5)\t0.137\t\nImmunoglobulin (IVIG)\t4 / 21 (19.0)\t4 / 68 (5.9)\t0.085\t\nSurgical interventions\t\t\t\t\nDebridement, drainage and/or amputation of extremities\t1 / 21 (4.8)\t11 / 43 (25.6)\t0.041\n**\n\n\t\nExploratory surgery (laparotomy)\t5 / 21 (23.8)\t26 / 43 (60.5)\t0.006\n*\n\n\t\nHysterectomy\t4 / 21 (19.0)\t20 / 43 (46.5)\t0.033\n*\n\n\t\nSurgical findings\t\t\t\t\nAscites or pus in the peritoneal cavity (included peritonitis)\t3 / 5 (60.0)\t8 / 12 (66.7)\t0.793\t\nNecrosis, inflammation, or exudate present in the uterus, ovaries and/or fallopian tubes\t4 / 6 (66.7)\t20 / 22 (90.9)\t0.191\t\nNormal placenta, uterus and/or pelvic organs\t2 / 6 (33.3)\t2 / 22 (9.1)\t0.191\t\nBacterial sources\t\t\t\t\nUrine\t0 / 22 (0.0)\t9 / 72 (12.5)\t0.080\t\nCervix, vagina, lochia\t9 / 22 (40.9)\t40 / 72 (55.6)\t0.229\t\nPeritoneum (ascites)\t2 / 22 (9.1)\t11 / 72 (15.3)\t0.368\t\nOropharynx or respiratory system\t5 / 22 (22.7)\t4 / 72 (5.6)\t0.030\n**\n\n\t\nBlood\t16 / 22 (72.7)\t45 / 72 (62.5)\t0.379\t\nCNS system\t1 / 22 (4.5)\t1 / 72 (1.4)\t0.415\t\nMaternal outcome\t\t\t\t\nSurvived\t10 / 25 (40.0)\t61 / 73 (83.6)\t0.000\n*\n\n\t\nDied\t15 / 25 (60.0)\t12 / 73 (16.4)\t\t\nFetal outcome\t\t\t\t\nSurvived\t7 / 25 (33.3)\t41 / 43 (95.3)\t0.000\n*\n\n\t\nDied\t14 / 25 (66.7)\t2 / 43 (4.7)\t\t\n* A two‐tailed paired Pearson's chi‐square test with α = 0.05, yielded a statistically significant P‐value. Actual values were noted in the table.\n\n** A one‐tailed paired Fisher's exact test with α = 0.05 yielded a statistically significant P‐value. Actual values were noted in the table.\n\n† Data were extracted as follows:\n\nA valid negative finding was recorded when at least one other positive or negative finding was reported for a specific category.\n\nData were recorded as missing when there were no findings reported for the category.\n\nCases in which a vasopressor was administered were recorded as having a 'systolic pressure <90 mmHg'.\n\nWhen numerical values were reported, the terms were defined as follows: fever, body temperature ≥ 37.5°C; hypotension, systolic pressure < 90 mmHg; tachycardia, heart rate ≥ 100 beats per minute; tachypnea, respiratory rate > 20 breaths per minute; shock, systolic pressure < 90 mmHg and heart rate ≥ 100 beats per minute.\n\nThus 'fever' could not be stratified as either ≥38.0°C or ≥ 39.0°C.\n\n‡ Missing data were excluded from the analysis. They were also excluded from each denominators.\n\nCases were described in Table 1.\n\nCNS, central nervous system; GAS, group A streptococcal; IVIG, intravenous immunoglobulin; qSOFA, quick sequential organ failure assessment; CENTOR, cough absent, exudate, nodes, temperature, young OR old modifier; WBC, white blood cell.\n\nUnivariate analysis was used to test the relationship between the maternal outcome and several clinical characteristics assumed to be potential risk factors (Table 3). Five clinical characteristics: antenatal onset, age of ≤19 or ≥ 35 years, cesarean section, qSOFA score of ≥2 and no surgical interventions were significantly associated with maternal death on univariate analysis. Next, multivariate analysis was performed with the abovementioned five clinical characteristics (Table 4). Antenatal onset and a qSOFA score of ≥2 were significantly and independently associated with maternal death (odds ratio [OR] = 7.922, 95% confidence interval [CI] = 1.297–48.374; P = 0.025, and OR = 6.166, 95% CI = 1.066–35.670; P = 0.042, respectively).\n\nTable 3 Clinical risk factors for perinatal GAS infection (univariate analysis)\n\nCharacteristics\tMaternal outcome\t\nP‐value\t\nSurvived (n = 71)\tDied (n = 27)\t\nAntenatal onset\t10 (14.1)\t15 (55.6)\t0.000\n*\n\n\t\nAge, ≤19 or ≥35 years\t16 (26.7)\t14 (53.8)\t0.015\n*\n\n\t\nMultiparous\t33 (76.7)\t15 (78.9)\t0.564\t\nCesarean section\t8 (13.1)\t7 (33.3)\t0.045\n**\n\n\t\nOnset during hospitalization\t20 (31.3)\t7 (26.9)\t0.685\t\nSore throat + CENTOR, ≥2\t6 (60.0)\t2 (28.6)\t0.218\t\nqSOFA score, ≥2\t11 (19.3)\t10 (58.8)\t0.003\n**\n\n\t\nNo surgical intervention\t14 (28.6)\t12 (63.2)\t0.008\n*\n\n\t\nPositive blood culture\t43 (62.3)\t18 (72.0)\t0.385\t\n* A two‐tailed paired Pearson's chi‐square test (α = 0.05) performed on this data yielded a statistically significant P‐value. Actual values were noted in the table.\n\n** A one‐tailed paired Fisher's exact test (α = 0.05) performed on this data yielded a statistically significant P‐value. Actual values were noted in the table.\n\nNumerical values were defined as n (%), and cases in which the indicated feature was not reported were not included in calculations.\n\nCENTOR, cough absent, exudate, nodes, temperature, young OR old modifier; GAS, group A streptococcal; qSOFA, quick sequential organ failure assessment.\n\nTable 4 Multivariate analysis evaluating risk factors for maternal mortality caused by perinatal GAS infection\n\nCharacteristics\tMaternal outcome\tOR\t95% CI\t\nP\n\t\nSurvived (n = 71)\tDied (n = 27)\t\nAntenatal onset\t10 (14.1)\t15 (55.6)\t7.922\t1.297–48.374\t0.025\n*\n\n\t\nqSOFA score, ≥2\t11 (19.3)\t10 (58.8)\t6.166\t1.066–35.670\t0.042\n*\n\n\t\nNo surgical intervention\t14 (28.6)\t12 (63.2)\tNG\tNG\tNG\t\nAge, ≤19 or ≥35 years\t16 (26.7)\t14 (53.8)\tNG\tNG\tNG\t\nCesarean section\t8 (13.1)\t7 (33.3)\tNG\tNG\tNG\t\n* Logistic regression analysis (α = 0.05) identified that antenatal onset and a qSOFA score of ≥2 were to be independent risk factors associated with maternal death in perinatal GAS infection.\n\nNumerical values were defined as n (%), and cases in which the indicated feature was not reported were not included in calculations.\n\nCI, confidence interval; GAS, group A streptococcal; NG, not given.\n\nDiscussion\nAntenatal onset and a qSOFA score of ≥2 were significantly associated with maternal death in our study. In the literature, Hamilton et al. reported the largest number of cases of perinatal GAS infections (67 patients, including 10 with antenatal infection) and noted that GAS infection during the third trimester was associated with maternal and fetal death,\n2\n whereas we reported a total of 98 patients, including 25 with antenatal infection. Of particular interest is the comparison between clinical characteristics and maternal outcome by multivariate analysis, which was not attempted in previous reports. Furthermore, few reports have included CENTOR criteria, defined as Cough absent, Exudate, Nodes, Temperature, young OR old modifier, and the qSOFA score as a clinical characteristic. Only Tanaka et al. examined the qSOFA score in maternal death cases.\n62\n\n\n\nWhy was antenatal GAS infection associated with poor maternal outcomes? Compared with postnatal cases, antenatal infections had initial symptoms outside of the hospital and the initiation of treatment might have been delayed. Generally, potentially invasive surgical treatment often makes physicians hesitant to operate upon pregnant patients.\n\nSecond, we assume there may be several types of perinatal GAS infection depending on the infection route, as well as the initial infection site. However, as is mentioned in previous article,\n63\n it is difficult to elucidate the route of infection of GAS, and we were not able to extract valid data from articles.\n\nWe next investigated potential indicators of risk that could be used to suspect a perinatal GAS infection in pregnant women. Although the CENTOR criteria is a diagnostic criterion for GAS pharyngitis and the qSOFA score is that for sepsis, we assumed that these criteria can be used for the detection of perinatal GAS infection. However, because of the limited data availability, we were not able to examine the sensitivity in this study. In antenatal cases, all the criteria in the qSOFA score (systolic pressure < 100 mmHg, respiratory rate > 22 breaths per minute and altered mental status) were available in 15 cases. Of these, 13 cases (86.7%) satisfied one or more criteria in qSOFA. Thus, we suggest that medical resources should be provided earlier to pregnant women who feel ill, and medical providers should triage using the qSOFA score. If a patient is positive for any of the qSOFA criteria, she should be immediately referred to a critical care medical center. Further study should be done because of the limited number of cases in this study.\n\nThere were some other limitations to our study that should be considered. Because patients from a wide time period were included, patients from a more recent chronological timeframe may have experienced better outcomes than those from an earlier chronological period. However, the maternal outcome was not related to the published year of the case report (P = 0.363, Mann Whitney U test). Since most cases did not fully describe all the data we required (respiratory rate, in particular) for the study, we were not able to exclude the possibility of selection bias. In addition, our two cases are not definite cases, but probable cases according to the definition of Streptococcal toxic shock syndrome.\n3\n Likewise, our analyses included the other 28 probable cases extracted from past articles.\n\nIn conclusion, antenatal GAS infection is more critical than postnatal GAS infection, and a qSOFA score of ≥2 is also potentially critical. We suggest that the presence of any of the qSOFA signs may represent a useful clinical marker for antenatal GAS infection among patients presenting at primary obstetric facilities.\n\nDisclosure\nThe authors report no conflict of interest.\n\nAcknowledgments\nWe acknowledge the contributions of doctors in our department who provided patient management during this study, also the contributions of doctors in our district for prompted referral and initial management. No funding was provided for this study.\n==== Refs\nReferences\n1 \n\nChuang \nI \n, \nVan Beneden \nC \n, \nBeall \nB \n\net al\nPopulation‐based surveillance for postpartum invasive group a streptococcus infections, 1995–2000\n. Clin Infect Dis \n2002 ; 35 : 665 –670\n.12203162 \n2 \n\nHamilton \nSM \n, \nStevens \nDL \n, \nBryant \nAE \n. Pregnancy‐related group a streptococcal infections: Temporal relationships between bacterial acquisition, infection onset, clinical findings, and outcome\n. Clin Infect Dis \n2013 ; 57 : 870 –876\n.23645851 \n3 \n\nLappin \nE \n, \nFerguson \nAJ \n. Gram‐positive toxic shock syndromes\n. Lancet Infect Dis \n2009 ; 9 : 281 –290\n.19393958 \n4 \n\nSinger \nM \n, \nDeutschman \nCS \n, \nSeymour \nCW \n\net al\nThe third international consensus definitions for sepsis and septic shock (Sepsis‐3)\n. JAMA \n2016 ; 315 : 801 –810\n.26903338 \n5 \n\nMcIsaac \nWJ \n, \nWhite \nD \n, \nTannenbaum \nD \n, \nLow \nDE \n. A clinical score to reduce unnecessary antibiotic use in patients with sore throat\n. CMAJ \n1998 ; 158 : 75 –83\n.9475915 \n6 \n\nNathan \nL \n, \nPeters \nMT \n, \nAhmed \nAM \n, \nLeveno \nKJ \n. The return of life‐threatening puerperal sepsis caused by group a streptococci\n. Am J Obstet Gynecol \n1993 ; 169 : 571 –572\n.8372865 \n7 \n\nDotters \nDJ \n, \nKatz \nVL \n. Streptococcal toxic shock associated with septic abortion\n. Obstet Gynecol \n1991 ; 78 : 549 –551\n.1870820 \n8 \n\nHasegawa \nJ \n, \nSekizawa \nA \n, \nYoshimatsu \nJ \n\net al\nCases of death due to serious group a streptococcal toxic shock syndrome in pregnant females in Japan\n. Arch Gynecol Obstet \n2015 ; 291 : 5 –7\n.25194311 \n9 \n\nMcHenry \nCR \n, \nAzar \nT \n, \nRamahi \nAJ \n, \nCollins \nPL \n. Monomicrobial necrotizing fasciitis complicating pregnancy and puerperium\n. Obstet Gynecol \n1996 ; 87 : 823 –826\n.8677102 \n10 \n\nBusowski \nMT \n, \nLee \nM \n, \nBusowski \nJD \n, \nAkhter \nK \n, \nWallace \nMR \n. Puerperal group a streptococcal infections: A case series and discussion\n. Case Rep Med \n2013 ; 2013 : 751329 .23710192 \n11 \n\nHirose \nY \n, \nShibuya \nH \n, \nOkazaki \nE \n\net al\nToxic shock‐like syndrome with flu‐like prodrome: A possible role of 'enhancing tissue focus' for streptococcal toxic shock\n. J Infect \n2001 ; 42 : 195 –200\n.11545551 \n12 \n\nImaeda \nT \n, \nNakada \nTA \n, \nAbe \nR \n, \nTateishi \nY \n, \nOda \nS \n. Veno‐arterial extracorporeal membrane oxygenation for Streptococcus pyogenes toxic shock syndrome in pregnancy\n. J Artif Organs \n2016 ; 19 : 200 –203\n.26758056 \n13 \n\nBelfrage \nE \n, \nAnzén \nB \n, \nJörbeck \nH \n, \nSterner \nG \n, \nMarland \nM \n. Streptococcal infections in late pregnancy and labor\n. Scand J Infect Dis Suppl \n1990 ; 71 : 79 –85\n.2287920 \n14 \n\nIchiyama \nS \n, \nNakashima \nK \n, \nShimokata \nK \n\net al\nTransmission of Streptococcus pyogenes causing toxic shock‐like syndrome among family members and confirmation by DNA macrorestriction analysis\n. J Infect Dis \n1997 ; 175 : 723 –726\n.9041354 \n15 \n\nOoe \nK \n, \nUdagawa \nH \n. A new type of fulminant group a streptococcal infection in obstetric patients: Report of two cases\n. Hum Pathol \n1997 ; 28 : 509 –512\n.9104954 \n16 \n\nCrum \nNF \n, \nChun \nHM \n, \nGaylord \nTG \n, \nHale \nBR \n. Group a streptococcal toxic shock syndrome developing in the third trimester of pregnancy\n. Infect Dis Obstet Gynecol \n2002 ; 10 : 209 –216\n.12648315 \n17 \n\nAlhousseini \nA \n, \nLayne \nME \n, \nGonik \nB \n, \nBryant \nD \n, \nPatwardhan \nS \n, \nPatwardhan \nM \n. Successful continuation of pregnancy after treatment of group a streptococci sepsis\n. Obstet Gynecol \n2017 ; 129 : 907 –910\n.28383376 \n18 \n\nMorgan \nPJ \n. Maternal death following epidural anaesthesia for caesarean section delivery in a patient with unsuspected sepsis\n. Can J Anaesth \n1995 ; 42 : 330 –334\n.7788829 \n19 \n\nBarnham \nMR \n, \nWeightman \nNC \n. Bacteraemic Streptococcus pyogenes infection in the peri‐partum period: Now a rare disease and prior carriage by the patient may be important\n. J Infect \n2001 ; 43 : 173 –176\n.11798254 \n20 \n\nPalep‐Singh \nM \n, \nJayaprakasan \nJ \n, \nHopkisson \nJF \n. Peripartum group a streptococcal sepsis: A case report\n. J Reprod Med \n2007 ; 52 : 977 –978\n.17977181 \n21 \n\nSugiyama \nT \n, \nKobayashi \nT \n, \nNagao \nK \n, \nHatada \nT \n, \nWada \nH \n, \nSagawa \nN \n. Group A streptococcal toxic shock syndrome with extremely aggressive course in the third trimester\n. J Obstet Gynaecol Res \n2010 ; 36 : 852 –855\n.20666956 \n22 \n\nGustafson \nLW \n, \nBlaakær \nJ \n, \nHelmig \nRB \n. Group A streptococci infection. A systematic clinical review exemplified by cases from an obstetric department\n. Eur J Obstet Gynecol Reprod Biol \n2017 ; 215 : 33 –40\n.28600919 \n23 \n\nStevens \nDL \n, \nTanner \nMH \n, \nWinship \nJ \n\net al\nSevere group A streptococcal infections associated with a toxic shock‐like syndrome and scarlet fever toxin A\n. N Engl J Med \n1989 ; 321 : 1 –7\n.2659990 \n24 \n\nOkumura \nK \n, \nSchroff \nR \n, \nCampbell \nR \n, \nNishioka \nL \n, \nElster \nE \n. Group A streptococcal puerperal sepsis with retroperitoneal involvement developing in a late postpartum woman: Case report\n. Am Surg \n2004 ; 70 : 730 –732\n.15328810 \n25 \n\nRaymond \nJ \n, \nSchlegel \nL \n, \nGarnier \nF \n, \nBouvet \nA \n. Molecular characterization of Streptococcus pyogenes isolates to investigate an outbreak of puerperal sepsis\n. Infect Control Hosp Epidemiol \n2005 ; 26 : 455 –461\n.15954483 \n26 \n\nAronoff \nDM \n, \nMulla \nZD \n. Postpartum invasive group A streptococcal disease in the modern era\n. Infect Dis Obstet Gynecol \n2008 ; 2008 : 796892\n10.1155/2008/796892 .19125207 \n27 \n\nPanaro \nNR \n, \nLutwick \nLI \n, \nChapnick \nEK \n. Intrapartum transmission of group a streptococcus\n. Clin Infect Dis \n1993 ; 17 : 79 –81\n.8353251 \n28 \n\nNguyen \nM \n, \nBendi \nVS \n, \nGuduru \nM \n\net al\nPostpartum invasive group A streptococcus infection: Case report and mini‐review\n. Cureus \n2018 ; 10 : e3184.30364777 \n29 \n\nJewett \nJF \n. Post‐cesarean sepsis\n. N Engl J Med \n1974 ; 291 : 1032 –1033\n.4415143 \n30 \n\nSlowey \nMJ \n, \nPiacquadio \nKM \n. Generalized Shwartzman reaction caused by group a beta‐hemolytic streptococcus, resulting in maternal death. A case report\n. J Reprod Med \n1994 ; 39 : 553 –556\n.7966050 \n31 \n\nCastagnola \nDE \n, \nHoffman \nMK \n, \nCarlson \nJ \n, \nFlynn \nC \n. Necrotizing cervical and uterine infection in the postpartum period caused by group a streptococcus\n. Obstet Gynecol \n2008 ; 111 : 533 –535\n.18239012 \n32 \n\nLee \nVH \n, \nSulis \nC \n, \nSayegh \nRA \n. Puerperal Group A Streptococcus infection: A case report\n. J Reprod Med \n2005 ; 50 : 621 –623\n.16220770 \n33 \n\nDehaene \nI \n, \nLoccufier \nA \n, \nTemmerman \nM \n, \nde Keersmaecker \nB \n, \nde Baene \nL \n. Creatine kinase as an indicator for hysterectomy in postpartum endomyometritis due to group A streptococci: A hypothesis illustrated by a case report\n. Gynecol Obstet Invest \n2012 ; 73 : 82 –88\n.22178984 \n34 \n\nNoronha \nS \n, \nYue \nCT \n, \nSekosan \nM \n. Puerperal group a beta‐hemolytic streptococcal toxic shock‐like syndrome\n. Obstet Gynecol \n1996 ; 88 : 728 .8841274 \n35 \n\nGergis \nH \n, \nBarik \nS \n, \nLim \nK \n, \nPorter \nW \n. Life‐threatening puerperal infection with group a streptococcus\n. J R Soc Med \n1999 ; 92 : 412 –413\n.10656011 \n36 \n\nStefonek \nKR \n, \nMaerz \nLL \n, \nNielsen \nMP \n, \nBesser \nRE \n, \nCieslak \nPR \n. Group A streptococcal puerperal sepsis preceded by positive surveillance cultures\n. Obstet Gynecol \n2001 ; 98 : 846 –848\n.11704180 \n37 \n\nGonzález Castro \nA \n, \nRodriguez‐Borregan \nJC \n, \nObeso \nT \n, \nCastellanos \nA \n, \nPerez‐Ceballos \nA \n, \nSesmero \nJR \n. Necrotizing fasciitis after cesarean section\n. Arch Gynecol Obstet \n2008 ; 277 : 579 –581\n.18004578 \n38 \n\nCooper \nJD \n, \nCooper \nSR \n, \nWolk \nD \n\net al\nPostpartum Streptococcus pyogenes outbreak in the labor and delivery unit of a quaternary referral center: A case series and review of the literature\n. Clin Microbiol Newsl \n2017 ; 39 : 11 –15\n.\n39 \n\nLurie \nS \n, \nVaknine \nH \n, \nIzakson \nA \n, \nLevy \nT \n, \nSadan \nO \n, \nGolan \nA \n. Group A Streptococcus causing a life‐threatening postpartum necrotizing myometritis: A case report\n. J Obstet Gynaecol Res \n2008 ; 34 : 645 –648\n.18840172 \n40 \n\nTurner \nCE \n, \nDryden \nM \n, \nHolden \nMT \n\net al\nMolecular analysis of an outbreak of lethal postpartum sepsis caused by Streptococcus pyogenes\n\n. J Clin Microbiol \n2013 ; 51 : 2089 –2095\n.23616448 \n41 \n\nSilver \nRM \n, \nHeddleston \nLN \n, \nMcGregor \nJA \n, \nGibbs \nRS \n. Life‐threatening puerperal infection due to group a streptococci\n. Obstet Gynecol \n1992 ; 79 : 894 –896\n.1565401 \n42 \n\nRowan \nJA \n, \nNorth \nRA \n. Necrotizing fasciitis in the puerperium\n. Am J Obstet Gynecol \n1995 ; 173 : 241 –242\n.7631696 \n43 \n\nJorup‐Rönström \nC \n, \nHofling \nM \n, \nLundberg \nC \n, \nHolm \nS \n. Streptococcal toxic shock syndrome in a postpartum woman. Case report and review of the literature\n. Infection \n1996 ; 24 : 164 –167\n.8740114 \n44 \n\nGolden \nS \n. Group a streptococcus and streptococcal toxic shock syndrome: A postpartum case report\n. J Midwifery Womens Health \n2003 ; 48 : 357 –359\n.14526350 \n45 \n\nTorda \nA \n. Postpartum toxic shock syndrome associated with multiple splenic infarcts\n. Med J Aust \n2005 ; 182 : 93 .\n46 \n\nYagi \nH \n, \nFukushima \nK \n, \nSatoh \nS \n, \nNakashima \nY \n, \nNozaki \nM \n, \nNakano \nH \n. Postpartum retroperitoneal fasciitis: A case report and review of literature\n. Am J Perinatol \n2005 ; 22 : 109 –113\n.15731991 \n47 \n\nde Moya \nMA \n, \ndel Carmen \nMG \n, \nAllain \nRM \n, \nHirschberg \nRE \n, \nShepard \nJAO \n, \nKradin \nRL \n. Case records of the Massachusetts General Hospital. Case 33‐2009. A 35‐year‐old woman with fever, abdominal pain, and hypotension after cesarean section\n. N Engl J Med \n2009 ; 361 : 1689 –1697\n.19846855 \n48 \n\nPark \nYS \n, \nOwen \nAM \n, \nAdno \nAM \n, \nMarry \nJ \n. Pyogenic pacroiliitis due to Group A Streptococcus following uncomplicated pregnancy and vaginal delivery\n. Case Rep Obstet Gynecol \n2013 ; 2013 : 981474 .24396619 \n49 \n\nKeogh \nJ \n, \nMacDonald \nD \n, \nKelehan \nP \n. Septic pelvic thrombophlebitis: An unusual treatable postpartum complication\n. Aust N Z J Obstet Gynaecol \n1993 ; 33 : 204 –207\n.8216128 \n50 \n\nSchummer \nW \n, \nSchummer \nC \n. Two cases of delayed diagnosis of postpartal streptococcal toxic shock syndrome\n. Infect Dis Obstet Gynecol \n2002 ; 10 : 217 –222\n.12648316 \n51 \n\nDaif \nJL \n, \nLevie \nM \n, \nChudnoff \nS \n, \nKaiser \nB \n, \nShahabi \nS \n. Group a streptococcus causing necrotizing fasciitis and toxic shock syndrome after medical termination of pregnancy\n. Obstet Gynecol \n2009 ; 113 : 504 –506\n.19155935 \n52 \n\nMartens \nPR \n, \nMullie \nA \n, \nGoessens \nL \n. A near‐fatal case of puerperal sepsis\n. Anaesth Intensive Care \n1991 ; 19 : 108 –110\n.2012267 \n53 \n\nSnabes \nMC \n, \nMartens \nMG \n. A severe puerperal group A streptococcal infection causing a toxic shock‐like syndrome\n. Int J Gynaecol Obstet \n1993 ; 40 : 245 –248\n.8096477 \n54 \n\nChristie \nJH \n, \nKeay \nSD \n, \nMorgan \nM \n, \nStorley \nR \n. Puerperal sepsis: A disease of the past?\n\nBJOG \n2001 ; 108 : 127 \n10.1111/j.1471-0528.2001.00046.x .\n55 \n\nKeller \nNA \n, \nGuan \nX \n, \nWiczulis \nA \n, \nBurcher \nP \n. Unexplained persistent postpartum palpitations and tachycardia due to Group A Streptococcus\n. BMC Res Notes \n2015 ; 8 : 731\n10.1186/s13104-015-1739-y .26619910 \n56 \n\nGourlay \nM \n, \nGutierrez \nC \n, \nChong \nA \n, \nRobertson \nR \n. Group A streptococcal sepsis and ovarian vein thrombosis after an uncomplicated vaginal delivery\n. J Am Board Fam Pract \n2001 ; 14 : 375 –380\n.11572543 \n57 \n\nFeigenberg \nT \n, \nSela \nHY \n, \nApplbaum \nYH \n, \nMankuta \nD \n. Puerperal widespread pyomyositis after group A streptococcal toxic shock syndrome\n. Isr Med Assoc J \n2008 ; 10 : 483 –484\n.18669156 \n58 \n\nSynnestvedt \nM \n, \nMüller \nF \n, \nGaustad \nP \n, \nBucher \nA \n. Recurrent group a streptococcal genital infection after puerperal sepsis\n. Scand J Infect Dis \n2003 ; 35 : 509 –510\n.14514155 \n59 \n\nWhitted \nRW \n, \nYeomans \nER \n, \nHankins \nGD \n. Group A beta‐hemolytic streptococcus as a cause of toxic shock syndrome. A case report\n. J Reprod Med \n1990 ; 35 : 558 –560\n.2191134 \n60 \n\nQuinney \nRA \n, \nAli \nMR \n, \nThomas \nMG \n, \nLang \nSD \n. Post‐partum streptococcal meningitis and septicaemia\n. N Z Med J \n1984 ; 97 : 702 –703\n.6384842 \n61 \n\nGriffiths \nAN \n, \nSudhahar \nAA \n, \nAshraf \nM \n. Neonatal necrotising fasciitis and late maternal pelvic abscess formation. A late complication of group a streptococcus\n. J Obstet Gynaecol \n2005 ; 25 : 197 –198\n.15814407 \n62 \n\nTanaka \nH \n, \nKatsuragi \nS \n, \nHasegawa \nJ \n\net al\nThe most common causative bacteria in maternal sepsis‐related deaths in Japan were group A Streptococcus: A nationwide survey\n. J Infect Chemother \n2019 ; 25 : 41 –44\n.30377069 \n63 \n\nMeleney \nFL \n. Hemolytic streptococcus gangrene\n. Arch Surg \n1924 ; 9 : 317 –364\n.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1341-8076",
"issue": null,
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "group A streptococcal infection; maternal sepsis; perinatal mortality",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": null,
"nlm_unique_id": "9612761",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32945073",
"pubdate": "2020-09-17",
"publication_types": "D016428:Journal Article",
"references": "8096477;12203162;22178984;8841274;6384842;15954483;14526350;19846855;8216128;2012267;12648315;2287920;11704180;26903338;1870820;9041354;19393958;26758056;19125207;23645851;10656011;26619910;11798254;8353251;23710192;7966050;9475915;25194311;15328810;28600919;23616448;20666956;4415143;8677102;28383376;18840172;9104954;1565401;8372865;16220770;11545551;15814407;8740114;18669156;12648316;7631696;30377069;30364777;11572543;15731991;17977181;7788829;19155935;18004578;18239012;11212990;14514155;2191134;24396619;2659990;15651973",
"title": "How could we suspect life-threatening perinatal group A streptococcal infection?",
"title_normalized": "how could we suspect life threatening perinatal group a streptococcal infection"
} | [
{
"companynumb": "JP-ROCHE-2789846",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
"drugadditional": null,
"dru... |
{
"abstract": "A patient in her 60s with systemic lupus erythematosus presented to an outpatient dermatology clinic on multiple occasions, with exacerbations of cutaneous lupus after exposure to surgical lighting during dental procedures. Her photosensitivity to surgical lighting suggests that artificial light sources pose potential triggers of lupus erythematosus in extra photosensitive individuals. This case report summarises those potential triggers and some options to decrease exposure from surgical lighting.",
"affiliations": "Corporal Michael J. Crescenz VA Medical Center Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA.;Corporal Michael J. Crescenz VA Medical Center Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Tiao|Janice|J|;Werth|Victoria P|VP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003729:Dental Care; D003748:Dental Equipment; D005260:Female; D006801:Humans; D008029:Lighting; D008178:Lupus Erythematosus, Cutaneous; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D010787:Photosensitivity Disorders",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26661286",
"pubdate": "2015-12-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "1642660;18992852;23281691;2649111;18756472;3702021;6644707;7639813;23253030;2742401;7138600;19183175;24617435;21535166",
"title": "Cutaneous lupus erythematosus flare following exposure to surgical light during a dental procedure.",
"title_normalized": "cutaneous lupus erythematosus flare following exposure to surgical light during a dental procedure"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-CO-PL-US-2016-038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
... |
{
"abstract": "Cryptococcosis is a common opportunistic infection in immunosuppressed patients. We present a case of cryptococcal meningitis with bilateral papillitis, multifocal choroiditis, and sensorineural hearing loss. The ocular manifestations present in this patient were unusual. The management of such cases poses a challenge because blindness and deafness can be the morbid sequelae.",
"affiliations": "Chest and Maternity Centre, Bangalore, India.",
"authors": "Satish|Kadappa S|KS|;Murthy|Krishna R|KR|;Yadav|Neha|N|;Murthy|Raghav A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0894",
"issue": "16(12)",
"journal": "The AIDS reader",
"keywords": null,
"medline_ta": "AIDS Read",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D002833:Choroiditis; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D015658:HIV Infections; D034381:Hearing Loss; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal; D010211:Papilledema",
"nlm_unique_id": "9206753",
"other_id": null,
"pages": "679-80, 682",
"pmc": null,
"pmid": "17195326",
"pubdate": "2006-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meningitis with papillitis, choroiditis, and hearing loss: an unusual presentation of cryptococcosis in HIV infection.",
"title_normalized": "meningitis with papillitis choroiditis and hearing loss an unusual presentation of cryptococcosis in hiv infection"
} | [
{
"companynumb": "IN-PFIZER INC-2020221651",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "Malignant ovarian germ cell tumours typically require multimodal therapy including surgery and systemic platinum-based chemotherapy. Most patients are cured, with survival rates exceeding 95%.\n\n\n\nThis report describes an unusual case of ovarian germ cell tumour (GCT) recurring 15 years after surgery and manifesting as metastatic disease to the liver, lung, and retroperitoneal lymph nodes.\n\n\n\nThymic hyperplasia was a confounding finding in this case, and it should be considered in the differential diagnosis of a mediastinal mass in heavily treated patients with GCT.",
"affiliations": "Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON.;Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON; Division of Medical Oncology, Department of Oncology, London Health Sciences Centre, London, ON.;Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON; Department of Pathology, London Health Sciences Centre, London, ON.;Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON; Division of Urology, Department of Surgery, London Health Sciences Centre, London, ON. Electronic address: nicholas.power@lhsc.on.ca.",
"authors": "Khan|Obaidullah|O|;Winquist|Eric|E|;Ettler|Helen|H|;Power|Nicholas|N|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2018.02.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": "40(10)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": null,
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D009373:Neoplasms, Germ Cell and Embryonal; D010051:Ovarian Neoplasms; D012008:Recurrence; D012186:Retroperitoneal Neoplasms; D013952:Thymus Hyperplasia; D055815:Young Adult",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "1329-1332",
"pmc": null,
"pmid": "30390946",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late Relapse of Ovarian Germ Cell Tumour.",
"title_normalized": "late relapse of ovarian germ cell tumour"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1009774",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant strain in a fully immunized young adult on long-term complement inhibitor therapy and daily penicillin chemoprophylaxis. Eculizumab is a humanized monoclonal antibody that binds human complement C5 protein and inhibits the terminal complement pathway. It is currently recommended for the treatment of complement-mediated thrombotic microangiopathies. An unwanted complication of inhibiting complement, however, is an increased risk of invasive meningococcal disease. Here, we report the first case of meningococcal group B vaccine failure in a young adult receiving eculizumab for atypical hemolytic uremic syndrome. She developed invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant meningococcal group B strain 4 months after receiving 2 doses of meningococcal group B vaccine while on oral penicillin prophylaxis against meningococcal infection.",
"affiliations": "Immunisation, Hepatitis, and Blood Safety Department, Public Health England, London, United Kingdom.;Vaccine Evaluation Unit, Public Health England, Manchester, United Kingdom.;Exeter Kidney Unit, Royal Devon and Exeter Hospital, Devon, United Kingdom.;Lister Renal Unit, Lister Hospital, Hertfordshire, United Kingdom.;Institute of Human Genetics, Newcastle University, Newcastle, United Kingdom; and.;Vaccine Evaluation Unit, Public Health England, Manchester, United Kingdom.;Immunisation, Hepatitis, and Blood Safety Department, Public Health England, London, United Kingdom; shamez.ladhani@phe.gov.uk.",
"authors": "Parikh|Sydel R|SR|;Lucidarme|Jay|J|;Bingham|Coralie|C|;Warwicker|Paul|P|;Goodship|Tim|T|;Borrow|Ray|R|;Ladhani|Shamez N|SN|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D022401:Meningococcal Vaccines; D010406:Penicillins; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2016-2452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "140(3)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D008589:Meningococcal Infections; D022401:Meningococcal Vaccines; D038541:Neisseria meningitidis, Serogroup B; D010403:Penicillin Resistance; D010406:Penicillins; D055815:Young Adult",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28864711",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meningococcal B Vaccine Failure With a Penicillin-Resistant Strain in a Young Adult on Long-Term Eculizumab.",
"title_normalized": "meningococcal b vaccine failure with a penicillin resistant strain in a young adult on long term eculizumab"
} | [
{
"companynumb": "PHHY2017GB200908",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nSpontaneous reporting on adverse drug reactions (ADR) has been established in Malaysia since 1987, and although these reports are monitored by the Malaysia drug monitoring authority, the National Pharmaceutical Control Bureau, information about ADRs in the paediatric patient population still remains unexplored. The aims of this study, therefore, were to characterize the ADRs reported in respect to the Malaysian paediatric population and to relate the data to specific paediatric age groups.\n\n\nMETHODS\nData on all ADRs reported to the National Pharmaceutical Control Bureau between 2000 and 2013 for individuals aged from birth to 17 years old were analysed with respect to age and gender, type of reporter, suspected medicines (using the Anatomical Therapeutic Chemical classification), category of ADR (according to system organ class) as well as the severity of the ADR.\n\n\nRESULTS\nIn total, 11,523 ADR reports corresponding to 22,237 ADRs were analysed, with half of these reporting one ADR per report. Vaccines comprised 55.7% of the 11,523 ADR reports with the remaining being drug related ADRs. Overall, 63.9% of ADRs were reported for paediatric patients between 12 and 17 years of age, with the majority of ADRs reported in females (70.7%). The most common ADRs reported were from the following system organ classes: application site disorders (32.2%), skin and appendages disorders (20.6%), body as a whole general disorders (12.8%) and central and peripheral nervous system disorders (11.2%). Meanwhile, ADRs in respect to anti-infectives for systemic use (2194/5106; 43.0%) were the most frequently reported across all age groups, followed by drugs from the nervous system (1095/5106; 21.4%). Only 0.28% of the ADR cases were reported as fatal. A large proportion of the reports were received from healthcare providers in government health facilities.\n\n\nCONCLUSIONS\nADR reports concerning vaccines and anti-infectives were the most commonly reported in children, and are mainly seen in adolescents, with most of the ADRs manifesting in skin reactions. The majority of the ADR reports were received from nurses in the public sector, reporting ADRs associated with vaccine administration. The low fatality rate of ADR cases reported could potentially be caused by reporting bias due to the very low reporting percentage from the private healthcare institutions. This study indicates that ADR rates among Malaysian children are higher than in developed countries. Constant ADR reporting and monitoring, especially in respect to paediatric patients, should be undertaken to ensure their safety.",
"affiliations": "Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.;Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.;Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.;Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.",
"authors": "Rosli|Rosliana|R|;Ming|Long Chiau|LC|http://orcid.org/0000-0002-6971-1383;Abd Aziz|Noorizan|N|;Manan|Mohamed Mansor|MM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0155385",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2724941410.1371/journal.pone.0155385PONE-D-15-39366Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationVaccinesMedicine and Health SciencesImmunologyVaccination and ImmunizationVaccinesMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationVaccinesPeople and PlacesPopulation GroupingsAge GroupsPeople and PlacesGeographical LocationsAsiaMalaysiaMedicine and Health SciencesPediatricsMedicine and Health SciencesPharmacologyDrugsMedicine and Health SciencesHealth CareHealth Care ProvidersNursesPeople and PlacesPopulation GroupingsProfessionsNursesPeople and PlacesPopulation GroupingsAge GroupsAdolescentsMedicine and Health SciencesPharmacologyDrug Research and DevelopmentDrug SafetyA Retrospective Analysis of Spontaneous Adverse Drug Reactions Reports Relating to Paediatric Patients Paediatric Adverse Drug Reaction ReportingRosli Rosliana 1http://orcid.org/0000-0002-6971-1383Ming Long Chiau 12*Abd Aziz Noorizan 1Manan Mohamed Mansor 13*1 \nDepartment of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia2 \nUnit for Medication Outcomes Research and Education (UMORE), Pharmacy, School of Medicine, University of Tasmania, Hobart, Australia3 \nSchool of Pharmacy, KPJ Healthcare University College, Nilai, Negeri Sembilan, MalaysiaYang Jinn-Moon EditorNational Chiao Tung University, TAIWANCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: RR NAA LCM MMM. Performed the experiments: RR. Analyzed the data: RR LCM MMM. Contributed reagents/materials/analysis tools: RR LCM MMM. Wrote the paper: RR LCM MMM.\n\n* E-mail: mmmanan2002@yahoo.com (MMM); longchiauming@gmail.com (LCM)1 6 2016 2016 11 6 e015538523 9 2015 27 4 2016 © 2016 Rosli et al2016Rosli et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nSpontaneous reporting on adverse drug reactions (ADR) has been established in Malaysia since 1987, and although these reports are monitored by the Malaysia drug monitoring authority, the National Pharmaceutical Control Bureau, information about ADRs in the paediatric patient population still remains unexplored. The aims of this study, therefore, were to characterize the ADRs reported in respect to the Malaysian paediatric population and to relate the data to specific paediatric age groups.\n\nMethods\nData on all ADRs reported to the National Pharmaceutical Control Bureau between 2000 and 2013 for individuals aged from birth to 17 years old were analysed with respect to age and gender, type of reporter, suspected medicines (using the Anatomical Therapeutic Chemical classification), category of ADR (according to system organ class) as well as the severity of the ADR.\n\nResults\nIn total, 11,523 ADR reports corresponding to 22,237 ADRs were analysed, with half of these reporting one ADR per report. Vaccines comprised 55.7% of the 11,523 ADR reports with the remaining being drug related ADRs. Overall, 63.9% of ADRs were reported for paediatric patients between 12 and 17 years of age, with the majority of ADRs reported in females (70.7%). The most common ADRs reported were from the following system organ classes: application site disorders (32.2%), skin and appendages disorders (20.6%), body as a whole general disorders (12.8%) and central and peripheral nervous system disorders (11.2%). Meanwhile, ADRs in respect to anti-infectives for systemic use (2194/5106; 43.0%) were the most frequently reported across all age groups, followed by drugs from the nervous system (1095/5106; 21.4%). Only 0.28% of the ADR cases were reported as fatal. A large proportion of the reports were received from healthcare providers in government health facilities.\n\nDiscussion\nADR reports concerning vaccines and anti-infectives were the most commonly reported in children, and are mainly seen in adolescents, with most of the ADRs manifesting in skin reactions. The majority of the ADR reports were received from nurses in the public sector, reporting ADRs associated with vaccine administration. The low fatality rate of ADR cases reported could potentially be caused by reporting bias due to the very low reporting percentage from the private healthcare institutions. This study indicates that ADR rates among Malaysian children are higher than in developed countries. Constant ADR reporting and monitoring, especially in respect to paediatric patients, should be undertaken to ensure their safety.\n\nhttp://dx.doi.org/10.13039/501100003093Ministry of Higher Education, MalaysiaAcademic and Research Assimilation grants: 600-RMI/DANA 5/3/ARAS (46/2015)Rosli Rosliana This work was supported by Academic and Research Assimilation grants: 600-RMI/DANA 5/3/ARAS (46/2015). The authors would like to express their gratitude to Ministry of Higher Education and Universiti Teknologi MARA (UiTM), Malaysia for financial support for this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nBackground\nAdverse drug reaction (ADR) is defined as any response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function [1]. ADRs in children are not uncommon, with the literature showing that the incidence of ADRs in children is around 9.5%, with serious reactions accounting for 12% of the total number of ADRs [2]. Despite the fact that ADRs commonly occur in children (about three times more frequently than in non-elderly adults), there is little information regarding the characteristics of ADRs in this population [3].\n\nThe information on ADRs provided by the pharmaceutical companies during the premarketing phase of drug development is inevitably minimal. Since clinical trials are conducted in a limited timeframe, some ADRs, especially serious and latent ones, may not have taken place. As a consequence, only mild/moderate or non-serious ADRs tend to be captured during the development phase[4]. In addition, due to ethical and safety issues, vulnerable populations such as children, pregnant women and the elderly are rarely included in clinical trials [5–7], raising concerns about the safety profile of these drugs in these population groups [8].\n\nInformation on the safety profiles of drugs used in real healthcare settings is, therefore, very important in assisting healthcare professionals in making clinical decisions. This information can be acquired through the reporting of ADRs and it is, therefore, crucial to encourage healthcare professionals, and the public, to report any ADR events. In order to develop a systematic database on ADRs, the WHO has initiated an international ADR collaborative pharmacovigilance centre to monitor ADRs from all over the world. Systematic data collection from all collaborative centres enables the WHO to analyse adverse events associated with the use of drugs, identify signals or emerging problems and communicate how to minimise or prevent harm.\n\nPharmacovigilance is defined as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem” [9]. In Malaysia, pharmacovigilance activities are controlled by the National Centre for Adverse Drug Monitoring, a division within the National Pharmaceutical Control Bureau (NPCB) [10]. Unlike in other countries, ADR reporting in Malaysia is done voluntarily through spontaneous reporting by healthcare professionals, medical support staff, pharmaceutical companies and consumers. The submission of ADR reports can be done online or manually to the secretariat in the NPCB. Since the establishment of this process in 1987, a growing number of ADRs have been reported, largely due to increased awareness of the importance of ADR reporting [10].\n\nDuring the study period, the total population of Malaysia comprised approximately 29.7 million inhabitants and it is estimated that 25% of these were aged from birth to 17 years old [11]. Since Malaysia is one of the countries within the WHO International Programme for International Drug Monitoring, the National Pharmacovigilance Centre should optimally send over 200 reports per million inhabitants per year to the WHO Collaborating Centre for International Drug Monitoring [12]. NPCB receives approximately 9000 to 11500 ADR reports annually, corresponding to between 300 and 387 reports per million inhabitants per year.\n\nAlthough studies have been conducted on the ADRs in children reported to the international and national databases, the findings cannot be generalized to Malaysian children [13–18]. The possible reasons for these divergent findings are differences in settings, time periods, patient populations of different sizes and age groups, and different types of reporters [17]. In addition, the Malaysian healthcare system is different from that of many other countries.\n\nLike other countries, the Malaysian healthcare system consists of two main sectors, namely the public and the private sectors. Nevertheless, the health system varies considerably from other countries in Southeast Asia since Malaysia has centralized the administration of its public sectors, which means that all the policy and programmes are centrally formulated and financed by the Ministry of Health. The public sector is fully funded by taxation and plays a major role in providing universal health services in Malaysia. In other words, patients who seek medical treatment from the government health facilities will only have to pay minimal fees as low as one Ringgit Malaysia (Malaysian currency which equivalent is to US$0.24), since other medical expenses, including the cost of the medications themselves are subsidized by the government. On the other hand the private sector is totally self-funded and patients need to pay for all their medical expenses, either by private health insurance or from their own pockets [19]. Patients who seek medical treatment in private health facilities have higher expectations and are more demanding since they are paying directly for their healthcare costs. Because of this, the private health facilities need to maintain their prestige in order to retain their current patients and attract new patients to their facilities.\n\nTo date, limited studies have been conducted on ADRs in Malaysian children. The aims of this study, therefore, were to characterize the ADRs reported in the Malaysian paediatric population and to relate the data to specific paediatric age groups. In this context, this study makes a crucial contribution to the provision of a detailed insight into the types of ADRs in Malaysian children by analysing ADRs in children reported to the Malaysian National Centre for Adverse Drug Reaction with respect to age and gender, type of reporters, suspected medicines, category of ADRs and severity of ADRs.\n\nMethods\nSetting\nThis was a retrospective study using the Malaysian ADR reports database, QUEST2. It is a repository governed by the National Centre for Adverse Drug Monitoring, National Pharmaceutical Control Bureau which is under the purview of Ministry of Health of Malaysia. The database or any data derived from QUEST2 are protected by relevant Malaysian laws (Control of Drugs and Cosmetics Regulation 1984). Researchers that are interested accessing this database could do so by obtaining permission from National Centre for Adverse Drug Monitoring. The QUEST2 system contains all spontaneous ADR reports in Malaysia, including those reported by healthcare professionals in government and/or private health facilities; other health care professionals, pharmaceutical companies and consumers. As of January 2014, the QUEST2 database contained almost 62,000 ADR reports received from all over Malaysia’s thirteen states and two federal territories. ADR reports submitted to the NPCB must include the following information: patient’s particulars, the suspected medicine(s), the presumed ADR(s) and the reporter’s details. Upon receipt of ADR reports, the information in the reports is assessed by trained staff at NPCB and all the findings in all reports are discussed at a meeting of the Malaysian Adverse Drug Reactions Advisory Committee prior to submission to the national drug control authority in Malaysia and to the World Health Organisation-Uppsala Monitoring Centre (WHO-UMC) situated in Sweden.\n\nApproval to conduct this study was obtained from the National Institute of Health and Medical Research and Ethics Committee in the Ministry of Health, prior to implementation of the study (NMRR-14-1231-21610). Permission to access to the QUEST2 database was also granted. The data were retrieved from the QUEST2 system according to the ADR registration number that had been assigned automatically upon data entry into the database system. No informed consent were obtained prior to analysis as the patient information was already anonymized upon data entry to the database system.\n\nData Extraction\nAll national pharmacovigilance centres (of which there are now more than 80 from all parts of the world) may either use WHO Adverse Drug Reactions Terminology (WHO-ART) or Medical Dictionary for Regulatory Activities (MedDRA) terms or codes for reporting to the WHO global individual case safety report database system, Vigibase [20]. Since, the National Centre for ADR Monitoring in Malaysia has been using WHO-ART for system organ class (SOC) classification in their reporting to WHO-UMC, the same classification for SOC (WHO-ART) was used in this study. Furthermore, as one of the member countries participating in the international drug monitoring programme, NPCB utilized the WHO-UMC causality assessment system for evaluation of ADR reports.\n\nData were extracted from the QUEST2 ADR database into Microsoft® Excel files using the following criteria: Anatomical Therapeutic Chemical (ATC) classification of medications, active substance of the medicines, ADRs coded according to WHO Adverse Reaction Terminology (WHO-ART) at the SOC level, patient’s details (age and gender), type of reporters and severity of ADRs. Severity is defined as the intensity of a specific ADR event and can be categorized as mild, moderate, severe and fatal [21]. For the purpose of this study, in order to present the large amount of data in a comprehensive way, the medicines about which the reported ADRs were presented at ATC level 2.\n\nThe material comprised all ADR reports on children from birth to 17 years of age reported to the QUEST system from 2000 to 2013. These ADR reports were then subdivided according to the age categories based on the International Conference on Harmonisation Guidelines on Clinical Investigation of Medicinal Products in the Paediatric Population: neonates ≤ 27 days; infants ≤ 23 months; children 2–11 years; adolescents 12–17 years [22].\n\nReports Excluded\nScreening for possible duplicates in the ADR registration number was done using the duplication tool application in Microsoft Excel 2013. Duplication of reports can occur in large compilations of data when reports of the same events are being entered by more than one person. ADR reports relating to non-Malaysian citizens and those that had not been reviewed by the Malaysian Adverse Drug Reactions Advisory Committeewere excluded from the study. Other ADR reports that were excluded were reports on food supplements, traditional and veterinary products. Reports with no information on patient’s age were also excluded from this study, along with ADRs caused by drug administration to mothers. In order to enhance the quality of the data included in this study, only ADRs with causality assessed as certain, probable or likely and possible were analysed.\n\nStatistics\nData on ADRs according to years, gender, age group, type of reporters, suspected medicines and category of ADRs were described as frequencies and percentages. The analysis was undertaken using Microsoft Excel 2013 and IBM SPSS Version 19.\n\nResults\nOverall Characterization of QUEST2 Reports\nFrom 2000 to 2013, NPCB received a total of 61996 reports from various sources all over Malaysia. Of these, 19.2% (n = 11932) were related to children. The following reports: ADRs with causality evaluated as either unlikely, conditional or unclassified and unassessable or unclassifiable (n = 173), ADRs due to drug administration to the mother (n = 128), non-citizen (n = 3) and non-drug products (n = 105) were excluded from the study. After exclusion of these reports, a total of 11523 (18.6%) reports remained for use in this analysis (refer to Fig 1).\n\n10.1371/journal.pone.0155385.g001Fig 1 Flow chart of methodology and ADR reports included in the present study.\nThe 11523 reports received reported a total of 22237 ADRs for individuals from birth to 17 years of age during the study period. On average, from 2000 to 2007, 195 reports (range 97 to 305) were submitted per year, meaning that the overwhelming majority of reports have been submitted in recent years, with a peak in 2011 (n = 3527). The northern region of Malaysia (covering the states of Kedah, Perlis, Penang and Perak) reported the most ADRs (53.3%) followed by the central region (covering the state of Putrajaya, Kuala Lumpur, Selangor; 18.4%) and the East Coast Region (covering the states of Terengganu, Pahang, Kelantan; 10.4%). The highest number of ADRs reports was received from the state of Penang (42.4%).\n\nHalf of the reports received by the NPCB documented one ADR per report. Reports with ≥ 5 types of ADRs were commonly reported in adolescents in the 12–17 year age group. More than half (55.7%) of the ADRs reported in children were related to vaccines. In the reports where gender was known, 70.7% of the child reports concerned females. In general, female children (73.0%) were commonly seen to experience ADRs related to vaccines while the males (86.9%) were more prone to develop ADRs following drug administration.\n\nGender and Age Group (Year 2000–2013 Comparison)\nTable 1 illustrates a steadily increasing trend in the number of ADR reports from 2001 to 2010 and then a sharp increment in 2011 which levelled off thereafter. The majority of the reported ADRs occurred in adolescents aged between 12 to 17 years old (63.9%), whilst the fewest ADRs were reported in the neonatal group (1.3%). For vaccines, ADRs were most commonly reported for adolescents aged between 12 and 17 years (88.3%), and more than 90% of these ADRs were experienced by female children. On the other hand, for drugs, ADRs were most frequently reported in children aged 2 to 11 years old (45.6%) and adolescents 12 to 17 years old (33.3%), with male children having a higher tendency to develop ADRs (55.2%).\n\n10.1371/journal.pone.0155385.t001Table 1 Number of ADRs by year, gender and age groups.\nVariables\t0–27 days\t28 days - 23 months\t2–11 years\t12–17 years\tCombined\t\nADR by year, n\t\t\t\t\t\t\n2000\t1\t19\t70\t25\t115\t\n2001\t1\t22\t52\t22\t97\t\n2002\t3\t43\t53\t32\t131\t\n2003\t6\t50\t65\t40\t161\t\n2004\t4\t49\t119\t49\t221\t\n2005\t11\t66\t134\t94\t305\t\n2006\t8\t47\t109\t82\t246\t\n2007\t3\t52\t138\t93\t286\t\n2008\t13\t100\t205\t154\t472\t\n2009\t19\t135\t287\t194\t635\t\n2010\t15\t157\t282\t579\t1033\t\n2011\t26\t182\t336\t2983\t3527\t\n2012\t0\t100\t383\t1770\t2253\t\n2013\t37\t309\t447\t1248\t2041\t\nADR reports, n (%)\t147 (1.3)\t1331 (11.5)\t2680 (23.3)\t7365 (63.9)\t11523 (100)\t\nGender, n (%)\t\t\t\t\t\t\nVaccines, total\t15 (0.2)\t387 (5.9)\t352 (5.4)\t5663 (88.3)\t6417 (100)\t\n Female\t6 (0.1)\t169 (2.8)\t141 (2.4)\t5633 (94.7)\t5949 (92.7)\t\n Male\t8 (1.9)\t205 (48.3)\t190 (44.8)\t21 (5.0)\t424 (6.6)\t\n Unknown\t1 (2.3)\t13 (29.5)\t21 (47.7)\t9 (20.5)\t44 (0.7)\t\nDrugs, total\t132 (2.6)\t944 (18.5)\t2328 (45.6)\t1702 (33.3)\t5106 (100)\t\n Female\t55 (2.5)\t385 (17.6)\t954 (43.4)\t802 (36.5)\t2196 (43.0)\t\n Male\t71 (2.5)\t541 (19.2)\t1332 (47.3)\t876 (31.1)\t2820 (55.2)\t\n Unknown\t6 (6.7)\t18 (20.0)\t42 (46.7)\t24 (26.7)\t90 (1.8)\t\nType of Reporter\nMore than 90% of the reports were sent by healthcare providers in government health facilities. Most of the reports were sent by nurses (36.7%) followed by pharmacists (30.2%) and doctors (21.8%). Other reporters consist of product holders (5.2%) and non-healthcare professionals (0.2%). There were only three reports from consumers. At the early phase of ADR reporting in Malaysia, most of the reports came from the doctors but the total number of reports from doctors has increased only marginally over the years. Reports received from pharmacists have increased significantly, however, until a peak in 2011. Reports from pharmacists dropped in 2012 before rising again in 2013. Reports from nurses, however, increased the most dramatically, with the first reports received from them in 2009, rising to a peak in 2011 before falling off.\n\nSystem Organ Class\nFrom the 11523 reports received by the NPCB, 22237 SOCs were reported. “Application site disorders’ (32.2%) were the most commonly reported for children, followed by Skin and Appendages Disorders (20.6%), Body as a Whole General Disorders (12.8%), Central and Peripheral Nervous System Disorders (11.2%) and Gastrointestinal Disorders (8.1%). To make the findings more meaningful, the SOCs for Drugs and Vaccines were analysed separately according to children’s age groups.\n\nTable 2 provides an overview of the reported ADRs related to vaccines and drugs classified by SOCs and distributed by age group. The total numbers of reported ADRs relating to vaccines and drugs are shown for all SOCs and age groups. From 6417 ADR reports received regarding vaccines, there were 13574 SOCs reported in the last 14 years. The most commonly reported SOCs for vaccines were Application Site Disorders (52.1%) and the other frequently reported reactions were injection site pain, injection site reaction, injection site rash and injection site pruritus Other common SOCs reported with their associated reactions were central and peripheral nervous system disorders (13.0%) (examples: dizziness and headache), body as a whole general disorders (12.5%) (examples: fever and asthenia), gastrointestinal system disorders (8.3%) (examples: nausea and vomiting) and musculo-skeletal system disorders (6.8%) (examples: myalgia and muscle weakness). All of these SOCs were mostly seen in adolescents aged 12 to 17 years old.\n\n10.1371/journal.pone.0155385.t002Table 2 System organ class for vaccines and drugs according to age group.\n System Organ Class (SOC)\tAge of Child\tTotal, n\t\n0-27days\t28 Days—23 Months\t2–11 Years\t12–17 Years\t\nA) Vaccines\t\t\t\t\t\t\nApplication Site Disorders\t0\t84\t147\t6845\t7076\t\nCentral & Peripheral Nervous System Disorders\t0\t132\t69\t1568\t1769\t\nBody as a Whole General Disorders\t7\t195\t230\t1264\t1696\t\nGastrointestinal System Disorders\t2\t56\t40\t1031\t1129\t\nMusculo-Skeletal System Disorders\t0\t7\t4\t910\t921\t\nSkin & Appendages Disorders\t14\t135\t46\t182\t377\t\nPsychiatric Disorders\t0\t16\t10\t346\t372\t\nRespiratory System Disorders\t0\t28\t9\t41\t78\t\nSecondary Term Events\t0\t5\t36\t1\t42\t\nPlatelet, Bleeding & Clotting Disorders\t0\t8\t8\t5\t21\t\nWhite Cell & Res Disorders\t0\t17\t1\t2\t20\t\nCardiovascular Disorders, General\t0\t11\t3\t4\t18\t\nResistance Mechanism Disorders\t0\t11\t5\t1\t17\t\nNeonatal & Infancy Disorders\t0\t6\t2\t0\t8\t\nHeart Rate & Rhythm Disorders\t0\t1\t0\t5\t6\t\nUrinary System Disorders\t0\t1\t4\t1\t6\t\nVision Disorders\t0\t0\t0\t4\t4\t\nMetabolic & Nutritional Disorders\t0\t3\t0\t1\t4\t\nVascular (Extracardiac) Disorders\t0\t1\t1\t1\t3\t\nEndocrine Disorders\t0\t1\t1\t0\t2\t\nRed Blood Cell Disorders\t0\t1\t0\t1\t2\t\nCollagen Disorders\t0\t0\t0\t1\t1\t\nHearing & Vestibular Disorders\t0\t1\t0\t0\t1\t\nLiver & Biliary System Disorders\t1\t0\t0\t0\t1\t\nTOTAL\t24\t720\t616\t12214\t13574\t\nB) Drugs\t\t\t\t\t\t\nSkin & Appendages Disorders\t69\t843\t2016\t1276\t4204\t\nBody as a Whole General Disorders\t10\t139\t551\t447\t1147\t\nCentral & Peripheral Nervous System Disorders\t10\t41\t321\t356\t728\t\nGastrointestinal System Disorders\t10\t88\t302\t277\t677\t\nRespiratory System Disorders\t13\t65\t176\t188\t442\t\nUrinary System Disorders\t14\t37\t143\t116\t310\t\nPsychiatric Disorders\t3\t16\t112\t85\t216\t\nVision Disorders\t0\t11\t88\t65\t164\t\nLiver & Biliary System Disorders\t0\t17\t38\t64\t119\t\nCardiovascular Disorders, General\t10\t29\t46\t23\t108\t\nApplication Site Disorders\t2\t7\t38\t34\t81\t\nHeart Rate & Rhythm Disorders\t5\t18\t23\t31\t77\t\nMetabolic & Nutritional Disorders\t1\t5\t39\t23\t68\t\nVascular (Extracardiac) Disorders\t1\t17\t24\t19\t61\t\nPlatelet, Bleeding & Clotting Disorders\t6\t12\t22\t17\t57\t\nMusculo-Skeletal System Disorders\t0\t0\t15\t33\t48\t\nRed Blood Cell Disorders\t1\t2\t13\t15\t31\t\nWhite Cell & Res Disorders\t1\t2\t10\t18\t31\t\nNeonatal & Infancy Disorders\t17\t5\t0\t0\t22\t\nResistance Mechanism Disorders\t2\t0\t4\t12\t18\t\nReproductive Disorders, Female\t0\t1\t2\t10\t13\t\nEndocrine Disorders\t1\t1\t2\t6\t10\t\nHearing & Vestibular Disorders\t0\t0\t3\t5\t8\t\nSecondary Term Events\t1\t0\t5\t2\t8\t\nFoetal Disorders\t1\t1\t3\t0\t5\t\nSpecial Senses Other Disorders\t0\t0\t2\t1\t3\t\nReproductive Disorders, Male\t0\t0\t2\t1\t3\t\nCollagen Disorders\t0\t0\t0\t2\t2\t\nMyo-, Endo, Pericardial & Valve Disorders\t0\t0\t1\t0\t1\t\nNeoplasms\t0\t0\t0\t1\t1\t\nTOTAL\t178\t1357\t4001\t3127\t8663\t\nUp to the year 2013, there were 5106 reports received by the NPCB related to drugs, with 8663 SOCs reported, with these being most common in children aged between 2 and 11 years old (46.2%). Unlike vaccines, SOCs from skin and appendages disorders (48.5%) which frequently manifested as rash urticarial, rash maculo-papular, pruritus and rash erythematous were the most common SOCs experienced by Malaysian children. Other common SOCs and their associated reactions were body as a whole disorders (13.2%) (fever), central peripheral nervous system disorders (8.4%) (oculogyric crisis), gastrointestinal system disorders (7.8%) (vomiting and diarrhoea) and respiratory system disorders (5.1%) (dyspnoea).\n\nAnatomical Therapeutic Chemical Classification\nThe most frequently reported agents belonged to the ‘Anti-infective for systemic use’ category (74.7%), and almost half of the reports were associated with vaccines (55.7%). Of these, viral vaccines contributed 52.4% of the reports followed by bacterial and viral (combined) (2.0%) and bacterial vaccines (1.3%). The largest proportion of ADR reports were received for Human papillomavirus (HPV) vaccine(87.6%). ADRs on vaccines were most frequently reported by nurses (65.6%) followed by pharmacists (15.7%). In the next stage of analysis, reports on vaccines were excluded and reports on drugs were further analysed according to age group.\n\nTable 3 displays the number of ADRs by therapeutic group (ATC Level 1) and age groups. Of the reported ADRs, 43% concerned Anti-infective for Systemic Use (ATC group J), which was the most frequently reported across all age groups, followed by drugs from the nervous system (ATC group N) (21.4%). Other therapeutic groups, namely Musculo-skeletal System (ATC group M) (7.6%), Alimentary Tract and Metabolism (ATC group A) (7.3%), Respiratory System (ATC group R) (7%) and Antineoplastic and Immunomodulating (ATC group L) (3.8%) were among the other common drugs reported for ADRs in Malaysian children.\n\n10.1371/journal.pone.0155385.t003Table 3 ADRs for drugs distributed by therapeutic group and age groups.\n*Therapeutic Group (ATC Level 1)\tAge of Child\tTotal, n\t\n0-27days\t28 Days—23 Months\t2–11 Years\t12–17 Years\t\nAnti-infectives for Systemic Use\t70\t588\t1010\t526\t2194\t\nNervous System\t12\t157\t478\t448\t1095\t\nMusculo-Skeletal System\t3\t20\t147\t216\t386\t\nAlimentary Tract & Metabolism\t7\t38\t157\t170\t372\t\nRespiratory System\t16\t58\t209\t75\t358\t\nAntineoplastic & Immunomodulating Agents\t2\t5\t111\t76\t194\t\nVarious\t0\t7\t58\t50\t115\t\nBlood & Blood Forming Organs\t2\t8\t34\t34\t78\t\nSystemic Hormones Preparations (excluding Gender Hormones & Insulins)\t0\t11\t32\t33\t76\t\nSensory Organs\t10\t34\t18\t8\t70\t\nCardiovascular Systems\t8\t8\t21\t27\t64\t\nDermatologicals\t2\t8\t27\t22\t59\t\nAntiparasitic Products, Insecticides & Repellents\t0\t3\t25\t11\t39\t\nGenito-Urinary System & Gender Hormones\t0\t0\t1\t5\t6\t\nTotal, n\t132\t945\t2328\t1701\t5106\t\n*Note the exclusion vaccine reports in these counts\n\nThe data were further analysed according to the six most common therapeutic groups in children (ATC Level 2), as shown in Table 4. The most common therapeutic groups reported for ADRs were anti-bacterials for systemic use (39.2%) followed by analgesics (9.6%). Other common therapeutic groups are anti-inflammatory and anti-rheumatic products (6.8%), anti-epileptics (6.4%), anti-neoplastic agents (3.4%), drugs for functional gastrointestinal disorders (3.5%), psycholeptics (3.1%), drugs for obstructive airway disease (3.5%), antihistamines for systemic use (2.4%) and antivirals for systemic use (2%). In terms of age, children in the 2 to 11 years age group were most commonly reported to experience ADRs from all the frequently reported therapeutic groups except for ADRs associated with musculo-skeletal drugs (n = 216) and alimentary tract and metabolism drugs (n = 170) which were more dominant in adolescents in the 12–17 years age group.\n\n10.1371/journal.pone.0155385.t004Table 4 ADRs by common therapeutic groups (ATC Level 2) and age groups.\nTherapeutic Group (ATC Level 2)\tAge of Child\tTotal, n\t\n0-27days\t28 Days—23 Months\t2–11 Years\t12–17 Years\t\nAnti-infectives for Systemic Use\t\t\t\t\t\t\nAntibacterials for systemic use\t69\t549\t908\t475\t2001\t\nAntivirals for systemic use\t0\t28\t58\t20\t106\t\nImmune sera & immunoglobulins\t1\t3\t21\t11\t36\t\nAntimycobacterials\t0\t2\t12\t14\t28\t\nAntimycotics for systemic use\t0\t6\t11\t6\t23\t\nTotal, n\t70\t588\t1010\t526\t2194\t\nNervous System\t\t\t\t\t\t\nAnalgesics\t3\t118\t223\t146\t490\t\nAntiepileptics\t2\t26\t146\t155\t329\t\nPsycholeptics\t4\t9\t48\t99\t160\t\nPsychoanaleptics\t2\t2\t41\t31\t76\t\nAnesthetics\t1\t2\t13\t8\t24\t\nOther nervous system drugs\t0\t0\t3\t7\t10\t\nAntiparkinsons\t0\t0\t3\t2\t5\t\nTotal, n\t12\t157\t478\t448\t1095\t\nAlimentary Tract & Metabolism\t\t\t\t\t\t\nDrugs for functional gastrointestinal disorders\t2\t14\t83\t79\t178\t\nDrugs for acid related disorders\t3\t3\t21\t41\t68\t\nVitamins\t1\t13\t23\t12\t49\t\nAntidiarrheals, intestinal antiinflamatory/antiinfective agents\t0\t4\t9\t6\t19\t\nMineral supplements\t1\t0\t3\t12\t16\t\nDrugs used in diabetes\t0\t2\t4\t10\t16\t\nAntiemetics & antinauseants\t0\t2\t6\t3\t11\t\nDrugs for constipation\t0\t0\t4\t4\t8\t\nOther alimentary tract & metabolism products\t0\t0\t2\t2\t4\t\nStomatological preparations\t0\t0\t1\t1\t2\t\nAnabolic agents for systemic use\t0\t0\t1\t0\t1\t\nTotal, n\t7\t38\t157\t170\t372\t\nMusculo-skeletal System\t\t\t\t\t\t\nAntiinflammatory & antirheumatic products\t2\t16\t132\t197\t347\t\nMuscle relaxants\t1\t4\t8\t10\t23\t\nOther drugs for disorders of the musculo-skeletal system\t0\t0\t3\t6\t9\t\nDrugs for treatment of bone disorders\t0\t0\t3\t1\t4\t\nTopical products for joint & muscular pain\t0\t0\t1\t2\t3\t\nTotal, n\t3\t20\t147\t216\t386\t\nRespiratory System\t\t\t\t\t\t\nDrugs for obstructive airway diseases\t4\t36\t111\t27\t178\t\nAntihistamines for systemic use\t6\t16\t71\t31\t124\t\nCough & cold preparations\t1\t5\t20\t15\t41\t\nNasal preparations\t0\t1\t7\t1\t9\t\nOther respiratory system products\t5\t0\t0\t0\t5\t\nThroat preparations\t0\t0\t0\t1\t1\t\nTotal, n\t16\t58\t209\t75\t358\t\nAntineoplastic & Immunomodulating Agents\t\t\t\t\t\t\nAntineoplastic agents\t0\t5\t104\t64\t173\t\nImmunosuppresants\t1\t0\t6\t6\t13\t\nImmunostimulants\t1\t0\t1\t6\t8\t\nTotal, n\t2\t5\t111\t76\t194\t\nOutcomes from ADRs\nOver 14 years, only 6.8% (drug, n = 676; vaccines, n = 106) of reported ADRs were categorized as severe, with a large proportion of ADRs categorized as mild or moderate. In the reports where outcomes were known, the majority of the ADRs reported for drugs (69.2%) and vaccines (10.5%) the patients recovered without sequalae. At the time of reporting, there were quite a number of ADRs concerned with drugs (20.5%) and vaccines (3%) where the patient is not yet recorded as recovered. A small proportion of fatal cases of ADRs were reported for both drugs (n = 28) and vaccines (n = 4), as shown in Table 5.\n\n10.1371/journal.pone.0155385.t005Table 5 Characteristics of fatal ADRs.\nSuspected Agents (Drug/Vaccine)\tAge\tGender\tYear\tAdverse Reactions (WHO-ART)\t\nCaused by ADR\t\t\t\t\t\n Ranitidine\t6 years\tFemale\t2000\tRespiratory depression, cardiac arrest\t\n Cisplatin\t6 years\tMale\t2000\tSteven Johnson Syndrome, death\t\n Phenytoin\t2 years\tFemale\t2001\tBradycardia\t\n Amoxycillin\t4 years\tFemale\t2007\tExanthema\t\n Imatinib\t17 years\tFemale\t2005\tJaundice, sepsis\t\n Suxamethonium\t15 years\tMale\t2009\tHypothermia, tachycardia, acidosis metabolic, hyponatremia, hypertension\t\n Azithromycin\t15 years\tFemale\t2008\tTachycardia ventricular\t\n Pneumococcal vaccine\t7 months\tMale\t2011\tInfection streptococcal\t\nDrug Maybe Contributory\t\t\t\t\t\n Beractant (4 cases)\t1 day\t3 female, 1 male\t2011\tPulmonary haemorrhage\t\n Metoclorpramide\t1 month\tFemale\t2011\tEnterocolitis necrotising\t\n Indomethacin\t2 weeks\tFemale\t2004\tRenal function abnormal\t\n Cyclophosphamide\t1 year\tFemale\t2012\tNeutropenia\t\n Promethazine\t1 year\tMale\t2001\tFace oedema, dyspnoea\t\n Midazolam\t7 years\tFemale\t2003\tApnoea\t\n Fentanyl\t4 years\tMale\t2011\tBradycardia, hypotension\t\n Doxorubicin\t8 years\tFemale\t2009\tCardiomyopathy\t\n Diphenhydramine\t2 years\tMale\t2008\tUnconsciousness, seizure anoxic, respiratory depression, limpness body, muscle stiffness, cardiac arrest, eye rolling, breathing arrested\t\n Carbamazepine immediate release tablet\t14 years\tMale\t2009\tToxic epidermal necrolysis\t\n Carbamazepine controlled release tablet\t14 years\tMale\t2009\tToxic epidermal necrolysis\t\n Sodium valproate\t12 years\tMale\t2004\tRenal failure, fever, jaundice, somnolence, rash erythematous, hepatic failure\t\n Gentamicin (2 cases)\t17 years\tMale\t2004\tRenal failure acute\t\n Lenograstim\t17 years\tFemale\t2006\tSepsis, Leukaemia acute megakaryocytic\t\n Cloxacillin\t14 years\tFemale\t2007\tRash\t\n Ceftriaxone\t13 years\tMale\t2008\tHepatic enzymes increased\t\n Meropenem\t1 months\tMale\t2005\tDiarrhoea, fever, colitis pseudomembranous, clostridial infection\t\n DTP*-Hib + Hep B\t3 months\tFemale\t2008\tSyncope, abnormal crying\t\n DTP*-Hib + Polio\t2 months\tMale\t2010\tAbnormal crying hypotonic-hyporesponsive episode, fits, eyes gaze upward, fever\t\n Hepatitis B\t1 month\tFemale\t2009\tVomiting, death\t\n*DTP-Hib-Diphtheria, Tetanus, Pertussis and Haemophilus influenzae type b\n\nMost fatal cases of ADRs were associated with the administration of Beractant (n = 4). Other commonly reported substances for fatal ADRs were Carbamazepine (n = 2), Bacterial and Viral Vaccines Combinations (n = 2) and Gentamicin (n = 2). Other substances, as depicted in Table 5, only reported a single fatal ADR case. Most fatalities were reported in adolescentsaged between 12 to 17 years old (n = 12). Children aged between 2 to 11 years and neonates reported the same number of fatalities while infants only reported four cases of fatalities.\n\nDiscussion\nOverall Characterization of QUEST2 Reports\nIn order to facilitate standard practice across the country, public health facilities are obliged to adopt the policy and programmes set by the Ministry of Health. Apart from the limited policy and fiscal freedom afforded to the local managers, the public sector needs to achieve national performance indicators and targets that are linked to their annual budget. ADR reporting performance is one of the major national key performance indicators which is monitored by the higher authorities in the Ministry, in order to strengthen the pharmacovigilance activity in Malaysia. Unlike with the public sector, the Ministry of Health only has minimal regulatory power over the private sector [23]. Due to this lack of control over the private sector, the reporting of ADRs from private health facilities is lower than from government health facilities. In this study, more than 90% of the ADRs received were from the government health facilities. The sharp increment of ADR reporting observed from 2009 was mainly due to the surge in the number of pharmacists and nurses in public healthcare institutions [24]. Moreover, the types of drugs suspected to cause ADRs are different between the two systems since the private health facilities do not have to comply with the standard national drug formulary established by the Ministry of Health [23]. The different types of medications suspected to cause ADRs in these two forms of healthcare provision were not the focus of this study, however.\n\nThe ADR data for local children is very important and each country should have their own data on ADRs in this specific population group. Based on the national income level, classified in accordance with the World Bank Definition, Malaysia is an upper middle-income country [23]. High income countries, primarily in Europe and the US, have greater resources, competency and infrastructure to survey the safety of medicine. There is, therefore, far more information available about ADRs from high income countries. Conversely, there is only limited information about ADRs occurring in middle to low-income countries, including Malaysia [25]. Although many drugs have been extensively studied in the developed countries, their safety profile cannot necessarily be generalised to other countries, where the incidence, pattern and severity of adverse reactions may differ markedly because of local environmental and genetic influences [26, 27].\n\nThe data presented here shows that there are substantial numbers of suspected ADRs, 18.6% (vaccine: 10.4%, drugs: 8.2%) in children reported in Malaysia. This figure is close to the incidence of patients with ADRs reported in a study conducted at a public hospital located in the central region of Malaysia (16.5%) [28]. The proportion of ADRs in children from other international pharmacovigilance centres was reported to range from 7–14.2%. The designs of these studies varied, however, in terms of sampling period, children’s age classifications and reported medications [14–16, 29]. With the exception of vaccines, the proportion of ADRs related to drugs (8.2%) in this study was slightly higher than that reported worldwide (7.7%) [16]. These ADRs occur in children at all age groups, and are noted to be from the therapeutic class of ‘anti-infectives for systemic use’, particularly vaccines (55.7%), and to cause a wide variety of reactions mainly from the SOC of “application site disorders’ (32.2%). In addition, the time period covered in this study is sufficient to witness the emerging role of nurses in the reporting of ADRs in Malaysia. This is because the nurse is the main healthcare professional that administers vaccine to the patient; especially nurses in primary and secondary healthcare institutes, such as district hospitals and clinics. Meanwhile, the high ADR reporting in the state of Penang as compared to the other states within Malaysia is mainly due to the strong ADR reporting culture among the senior medical specialists and pharmacists in two tertiary public hospitals there. This culture feeds through to junior medical staff, including nurses, who are taught and encouraged to submit ADRs that they encounter.\n\nGender and Age Groups\nIn this study, more than 50% of the ADRs involving children were for females, with an even greater proportion in the oldest age group (12–17 years old). Most of the ADRs (92.7%) reported were related to vaccines. The reason for this dominance was the introduction of Malaysia's cervical cancer prevention programme instituting free HPV immunisation to 13 years old Malaysian girls, which started in 2010 [30]. Other studies have also shown female dominance for ADRs related to vaccine administration [31].\n\nOn the contrary, a higher reporting rate for males was reported by Rashed et al. [32]. A similar trend of higher prevalence of ADRs among males, particularly those in the 2 to 11 years age groups, was also observed in two studies that included data from European and Vigibase member countries [16, 31]. Apart from the common prevalence of certain childhood diseases such as asthma and attention deficit hyperactivity disorder among males, no definite explanation for this difference has been identified [16, 31]. Meanwhile, the current study showed a higher prevalence of ADRs among adolescents 12–17 years; in contrast to worldwide Vigibase and Danish data that mostly consist of younger age groups (≤ 2 years old) [16, 17].\n\nType of Reporter\nThe initiatives taken by the NPCB through continuous ADR awareness programmes has resulted in a steady increase of ADR reporting over the years, with the majority of the reports now received from the pharmacists [24, 33]. ADR reporting activity has been included as part of pharmacist training modules, which possibly explains the high reporting rate among pharmacists. Although physicians are traditionally the primary reporters for ADRs in children, this study shows that, in a Malaysian context, nurses reported the most ADRs [16].The involvement of nurses in ADR reporting started in 2009 and this study discovers a dramatic increase in ADRs reporting by the nurses since 2010. Apart from ongoing awareness efforts by the NPCB, the dramatic rise of ADRs in 2010 and 2011 was a result of high reporting of ADRs related to HPV immunisation, as well as the administration of the H1N1 vaccines due to the H1N1 pandemic [34]. The same finding was reported by a study conducted in the UK, where the high volume of reports was attributed to a national immunization programme or campaign [29]. Although overall ADR reports received by the NPCB increased every year, a drop of 40% in ADRs related to vaccine administration was seen in 2012 [35]. Since paediatric ADRs mostly developed following immunisation, the low reporting of ADRs related to vaccines in that particular year has contributed to a drop of ADRs for children in 2012.\n\nEven though, the target of more than 200 reports per million population has been exceeded, the low rate of ADR reporting among private healthcare professionals, in spite its ADRs awareness efforts, is a cause for concern and the NPCB has now extended its ADR programmes to universities and professional medical and nursing associations. Other initiatives include the development of an online reporting system and ADR reporting promotion to community pharmacists through its professional association’s bulletin [24, 35].\n\nA study conducted among physicians in one of the university hospitals in Malaysia revealed that a high proportion of suspected ADRs were not reported due to uncertainty as to the types of reactions to report (81.4%) and a lack of awareness on the importance of ADR reporting (40%) [36]. These findings could now be obsolete, however, since this study was conducted in 2007, and there have been significant efforts to increase awareness among healthcare providers since then. Future study needs to be undertaken to assess the impact of NPCB awareness initiatives, however, and to identify factors that prohibit private healthcare providers from reporting ADR events.\n\nSystem Organ Class\nUnlike most studies, which utilize the MEdRA for ADR SOC classification, the WHO-ART was used in this study as this classification is used by NPCB in its routine ADRs reporting to WHO-UMC. Nevertheless, similar to other studies, the most frequently reported SOCs in children were related to skin reactions and administration site conditions, nervous system disorders and general disorders [15, 16].\n\nAnatomical Therapeutic Chemical Classification\nThe data from the current study revealed that routine administration of vaccines is associated with a large number of ADR reports, dwarfing the number of reports for medications. This reflects the high usage of vaccines in the paediatric population compared with medicines. The high volume of paediatric ADR reports in respect to vaccines has also been noted in other studies reviewing national pharmacovigilance databases [15, 17, 31].\n\nWhen the data were further broken down to therapeutic group (ATC Level 2), with the exception of vaccines, antibacterial drugs for systemic use appear to be the most prominent drugs suspected of causing ADRs in children, followed by drugs from the nervous system therapeutic group. Indeed, drug utilization studies of children in European countries show that the most commonly prescribed drugs are antibiotics [37]. This finding was also in line with the finding of an exploratory study on paediatric ADRs from the Vigibase system [15–17].\n\nIn the current study, the most common drugs associated with ADRs were among the most commonly utilized drugs in Malaysia as reported in the National Medicines Use Survey (NMUS), except for antivirals for systemic use and antineoplastics. The NMUS, which was designed to support the implementation of the National Medicines Policy, collects information on the supply, procurement, prescription, dispensing and use of drugs in Malaysia [38, 39]. Although information from the NMUS can be used for estimating the degree of underreporting of ADRs, and the number of people exposed to certain medications in the occurrence of ADRs, this information is inconsequential for the paediatric population. The NMUS uses Defined Daily Doses (DDD), the assumed average maintenance dose per day, as its main indication in adults in reporting drug utilization, and this makes it impossible to estimate the prevalence of drug use in paediatrics. In addition, the survey only provides information on medicines that have been procured or prescribed or dispensed, and this does not necessarily equate to medication actually consumed by patients. A national survey using information on prescribed daily dosages and indications should be initiated and compared with the DDD values so as to get accurate drug utilization figures for the Malaysian paediatric population [39–41].\n\nOutcomes from ADRs\nSimilar to other studies, a large number of the ADRs reported had mild outcomes, with only a small number being severe [18]. The current study revealed that the majority of the fatal ADRs were associated with drug rather than vaccine administration. In Malaysia, there were 32 fatal ADRs (0.28%) during the study period, which was lower than reported in other published literature (0.77% - 1.15%) [15, 17]. Although other studies have shown the majority of fatal cases to occur in younger childhood, this study found more fatalities in adolescents than in younger age groups [15]. The higher proportion of fatal cases in adolescents could be a result of the higher proportion of ADRs reported to the pharmacovigilance centre for this age group which has been shown in an international multicentre study [28]. Even though anticonvulsant administration in a paediatric context has been noted to cause the highest rate of fatalities, there were only four reported fatalities associated with anticonvulsants [42].\n\nThis study presents the overall reporting of ADRs for children in the Malaysian ADR database (the QUEST2 system) and only reports the incidence of ADRs in children, types and severity of ADRs and the most common drugs associated with ADRs. The current study presents the first large-scale data on ADR reported in children nationally. Studies monitoring specific childhood age groups, especially in respect to children below 2 years old could provide more useful information since the wider literature has reported more ADRs in this population group than has been shown in the current study.\n\nThe variation of risks for ADRs in different childhood age groups, and details regarding the management of the reaction, were not studied however, since some of these data were not readily available. In addition, the possible causal association between a medicine or vaccine and the suspected ADR was not formally assessed since the study only analysed the characteristics of suspected ADRs reported to NPCB. Furthermore, the relationship between the use of off-labelled drugs and the occurrence of ADRs were not studied since the list of off-labelled drugs is not well defined in Malaysia.\n\nThe data are derived entirely from the Malaysian ADR spontaneous reporting database and are therefore subject to the limitations of any such system. Those limitations highlighted in the literature include under-reporting of ADRs, variable quality in the completion of the reporting form, reporting biases, inability to calculate the true incidence of any ADRs reported, assessment of causality between a drug and an ADR and difficulty in identifying ADRs with long latency periods following the use of a drug [42–45].\n\nConclusions\nA sharp increase in ADR reporting in respect to children over the last 14 years was observed in Malaysia. The majority of ADRs reported for children were related to the use of vaccines and anti-infectives in adolescents. In lieu of that, the prevalence of fatality caused by reported ADRs in Malaysia is lower than the benchmark of developed countries. Most suspected ADRs were related to vaccines, which is linked to the emerging role played by nurses in the spontaneous reporting of ADRs.\n\nThe authors would like to thank the Director-General of Health Malaysia and Senior Director of Pharmaceutical Services, Ministry of Health (Malaysia) for the permission to conduct this study. We wish to thank Mr. Tan Ann Ling, Director of NPCB and staffs at National Centre for Adverse Drug Reaction Monitoring, NPCB (Sameerah Shaikh Abdul Rahman, Rokiah Isahak, Noraisyah Mohd Sani, Nurul Huda Hamdan and Wo Wee Kee) for providing technical support. Special appreciation goes to Prof Kamaruzaman Jusoff, Faculty of Resource Science and Technology, Universiti Malaysia Sarawak (UNIMAS) and Dr Jonathan Richardson (Academic Research Editors) for reviewing and editing the manuscript.\n==== Refs\nReferences\n1 WHO. International Drug Monitoring: The Role of National Centre (pp. 1–48). 1972.\n2 Impicciatore P , Choonara I , Clarkson A , Provasi D , Pandolfini C , Bonati M . Incidence of adverse drug reactions in paediatric in/out-patients: a systematic review and meta-analysis of prospective studies . Br J Clin Pharmacol . 2001 ;52 (1 ):77 –83 . 11453893 \n3 Du W , Lehr VT , Lieh-Lai M , Koo W , Ward RM , Rieder MJ , et al\nAn algorithm to detect adverse drug reactions in the neonatal intensive care unit . J Clin Pharmacol . 2013 ;53 (1 ):87 –95 . 10.1177/0091270011433327 .23400748 \n4 Aagaard L , Soendergaard B , Stenver DI , Hansen EH . Knowledge creation about ADRs—turning the perspective from the rear mirror to the projector? \nBr J Clin Pharmacol . 2008 ;65 (3 ):364 –76 . 10.1111/j.1365-2125.2007.03019.x \n17961195 \n5 Smyth RL , Weindling AM . Research in children: ethical and scientific aspects . Lancet . 1999 ;354 \nSuppl 2 :SII21 –4 . .10507255 \n6 Sammons HM . Avoiding clinical trials in children . Arch Dis Child . 2011 ;96 (3 ):291 –2 . 10.1136/adc.2010.203737 .21262747 \n7 Nor Aripin KN , Choonara I , Sammons HM . Systematic review of safety in paediatric drug trials published in 2007 . Eur J Clin Pharmacol . 2012 ;68 (2 ):189 –94 . 10.1007/s00228-011-1112-6 \n21858432 \n8 Sammons HM , Choonara I . Clinical trials of medication in children, 1996–2002 . Eur J Clin Pharmacol . 2005 ;61 (2 ):165 –7 . 10.1007/s00228-005-0894-9 .15761753 \n9 WHO. The importance of Pharmacovigilance: Safety monitoring of medicinal products (p. 7). 2002.\n10 Pharmacutical Services Division Ministry of Health Malaysia. Malaysian Guidelines for the Reporting and Monitoring of ADR. 2002. Available: http://www.bpfk.gov.my/madrac. Assessed 30 May 2015.\n11 Department of Statistics Malaysia. Malaysia Statistical Handbook. (pp. 1–134). 2014.\n12 WHO. Reporting Trends. WHO-Uppsala Monitoring Centre. 2015.\n13 Thiessard F , Roux E , Miremont-Salamé G , Fourrier-Réglat A , Haramburu F , Tubert-Bitter P , et al\nTrends in Spontaneous Adverse Drug Reaction Reports to the French Pharmacovigilance System (1986–2001) . Drug Saf . 2005 ;28 (8 ):731 –40 . 16048358 \n14 Wallerstedt SM , Brunlof G , Sundstrom A . Rates of spontaneous reports of adverse drug reactions for drugs reported in children: a cross-sectional study with data from the Swedish adverse drug reaction database and the Swedish Prescribed Drug Register . Drug Saf . 2011 ;34 (8 ):669 –82 . 10.2165/11591730-000000000-00000 .21751827 \n15 Aldea A , Garcia Sanchez-Colomer M , Fernandez Quintana E , Garcia Saiz M . Paediatric adverse drug reactions reported to the Spanish Pharmacovigilance System from 2004 to 2009 . Eur J Clin Pharmacol . 2012 ;68 (9 ):1329 –38 . 10.1007/s00228-012-1255-0 .22415248 \n16 Star K , Norén GN , Nordin K , Edwards IR . Suspected adverse drug reactions reported for children worldwide . Drug Saf . 2011 ;34 (5 ):415 –28 . 10.2165/11587540-000000000-00000 \n21513364 \n17 Aagaard L , Weber CB , Hansen EH . Adverse drug reactions in the paediatric population in Denmark: a retrospective analysis of reports made to the Danish Medicines Agency from 1998 to 2007 . Drug Saf . 2010 ;33 (4 ):327 –39 . 10.2165/11319100-000000000-00000 .20297864 \n18 Barzaga Arencibia Z , Lopez Leyva A , Mejias Pena Y , Gonzalez Reyes AR , Fernandez Manzano E , Choonara I . Pharmacovigilance in children in Camaguey Province, Cuba . Eur J Clin Pharmacol . 2012 ;68 (7 ):1079 –84 . 10.1007/s00228-012-1222-9 \n22315149 \n19 Jaafar S , Noh KM , Muttalib KA , Othman N , Healy J . Chapter 2: Organization and governance. In Malaysian Health System Review . Health Syst Transit . 2013 ;3 (1 ):15 –30 . Available: http://iris.wpro.who.int/bitstream/handle/10665.1/5283/9789290615842_eng.pdf?sequence=1.\n20 Lindquist M . VigiBase, the WHO global ICSR database system: basic facts . Drug Inform J . 2008 ;42 (5 ):409 –19 .\n21 Hartwig SC , Siegel J , Schneider PJ . Preventability and severity assessment in reporting adverse drug reactions . Am J Hosp Pharm . 1992 ;49 (9 ):2229 –32 . .1524068 \n22 International Conference on Harmonisation. Clinical Investigation of Medicinal Products in the Paediatric Population (E11). 2000. Available: http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/clinical-investigation-of-medicinal-products-in-the-pediatric-population.html. Accessed 12 Dec 2015.\n23 WHO . Malaysia Health System Review . Health Syst Transit . 2013 ;3 (1 ):1 –103 .\n24 Hadi M , Ming L . Impact of pharmacist recruitment on ADR reporting: Malaysian experience . South Med Rev . 2011 ;4 :55 –6 .\n25 Aagaard L , Strandell J , Melskens L , Petersen PS , Holme Hansen E . Global patterns of adverse drug reactions over a decade: analyses of spontaneous reports to VigiBase . Drug Saf . 2012 ;35 (12 ):1171 –82 . 10.2165/11631940-000000000-00000 .23072620 \n26 Eliasson E . Ethnicity and adverse drug reactions . BMJ . 2006 ;332 (7551 ):1163 –4 . 10.1136/bmj.332.7551.1163 \n16709964 \n27 Salmasi S , Khan TM , Hong YH , Ming LC , Wong TW . Medication errors in the Southeast Asian countries: a systematic review . PLoS One . 2015 ;10 (9 ):e0136545 \n10.1371/journal.pone.0136545 \n26340679 \n28 Rashed AN , Wong IC , Cranswick N , Tomlin S , Rascher W , Neubert A . Risk factors associated with adverse drug reactions in hospitalised children: international multicentre study . Eur J Clin Pharmacol . 2012 ;68 (5 ):801 –10 . Epub 2011/12/15. 10.1007/s00228-011-1183-4 .22166934 \n29 Hawcutt DB , Mainie P , Riordan A , Smyth RL , Pirmohamed M . Reported paediatric adverse drug reactions in the UK 2000–2009 . Br J Clin Pharmacol . 2012 ;73 (3 ):437 –46 . 10.1111/j.1365-2125.2011.04113.x \n21988288 \n30 Malaysia MoH. Annual Report: Noncommunicable Disease (NCD) Section (pp. 1–64). 2010.\n31 Blake KV , Zaccaria C , Domergue F , La Mache E , Saint-Raymond A , Hidalgo-Simon A . Comparison between paediatric and adult suspected adverse drug reactions reported to the European medicines agency: implications for pharmacovigilance . Paediatr Drugs . 2014 ;16 (4 ):309 –19 . 10.1007/s40272-014-0076-2 .24898717 \n32 Rashed AN , Wong IC , Cranswick N , Hefele B , Tomlin S , Jackman J , et al\nAdverse Drug Reactions in Children—International Surveillance and Evaluation (ADVISE): a multicentre cohort study . Drug Saf . 2012 ;35 (6 ):481 –94 . Epub 2012/05/23. 10.2165/11597920-000000000-00000 .22612852 \n33 Hadi MA , Helwani R , Long CM . Facilitators and barriers towards adverse drug reaction reporting: perspective of Malaysian hospital pharmacists . J Pharm Health Serv Res . 2013 ;4 (3 ):155 –8 . 10.1111/jphs.12022 \n34 National Pharmaceutical Control Bureau. Annual Report, Ministry of Health Malaysia. 2011.\n35 National Pharmaceutical Control Bureau. Annual Report, Ministry of Health Malaysia. 2012.\n36 Aziz Z , Siang TC , Badarudin NS . Reporting of adverse drug reactions: predictors of under-reporting in Malaysia . Pharmacoepidemiol Drug Saf . 2007 ;16 (2 ):223 –8 . 10.1002/pds.1313 .16947117 \n37 Sturkenboom MC , Verhamme KM , Nicolosi A , Murray ML , Neubert A , Caudri D , et al\nDrug use in children: cohort study in three European countries . BMJ . 2008 ;337 :a2245 \n10.1136/bmj.a2245 \n19029175 \n38 Roughead EE , Lhazeen K , Socialine E , Bahri S , Park BJ , Holloway K . Monitoring medicines use to support national medicines policy development and implementation in the Asia Pacific region . WHO South East Asia J Public Health . 2013 ;2 (2 ).\n39 Ministry of Health Malaysia. Malaysian Statistics on Medicines 2009–2010. 2010.\n40 Organization WH. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD index 2011. 2011.\n41 WHO Collaborating Centre for Drug Statistics Methodology . WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016 , 19th ed. \nWorld Health Organization , Oslo \n2015 Available: http://www.whocc.no/filearchive/publications/2016_guidelines_web.pdf. Accessed 10 Jan 2016.\n42 Clarkson A , Choonara I . Surveillance for fatal suspected adverse drug reactions in the UK . Arch Dis Child . 2002 ;87 (6 ):462 –6 . 12456539 \n43 Hazell L , Shakir SA . Under-reporting of adverse drug reactions: a systematic review . Drug Saf . 2006 ;29 (5 ):385 –96 . .16689555 \n44 Goldman SA . Limitations and strengths of spontaneous reports data . Clin Ther . 1998 ;20 \nSuppl C :C40 –4 . .9915089 \n45 Belton KJ . Attitude survey of adverse drug-reaction reporting by health care professionals across the European Union. The European Pharmacovigilance Research Group . Eur J Clin Pharmacol . 1997 ;52 (6 ):423 –7 . .9342576\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(6)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D016907:Adverse Drug Reaction Reporting Systems; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008296:Malaysia; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0155385",
"pmc": null,
"pmid": "27249414",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "10507255;11453893;12456539;1524068;15761753;16048358;16689555;16709964;16947117;17961195;19029175;20297864;21262747;21513364;21751827;21858432;21988288;22166934;22315149;22415248;22612852;23072620;23093890;23400748;24898717;26340679;28612769;9342576;9915089",
"title": "A Retrospective Analysis of Spontaneous Adverse Drug Reactions Reports Relating to Paediatric Patients.",
"title_normalized": "a retrospective analysis of spontaneous adverse drug reactions reports relating to paediatric patients"
} | [
{
"companynumb": "MY-ABBVIE-16P-101-1663845-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BERACTANT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBreast cancer is one of the most common cancers diagnosed during pregnancy. Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within 12 months of delivery. Nowadays PABC can be safely diagnosed, staged, and treated during pregnancy with good outcomes for both the mother and the fetus. Recent studies suggest that prognosis of women diagnosed during postpartum seems to be worse. In order to gain a better understanding of the PABC, we reviewed our centre's experience.\n\n\nMETHODS\nWe assessed the clinicopathological parameters, evolution, and outcome of patients treated in the Fundación Instituto Valenciano de Oncología of Valencia, Spain, from October 1990 to October 2013, and compared the results of patients diagnosed during pregnancy (group 'A') and patients diagnosed within one year of delivery (group 'B'). Of 12,000 cases of breast cancer registered in our database, 35 cases of PABC were identified. We included 11 patients in group 'A' and 24 in group 'B'.\n\n\nRESULTS\nIn our group the median age was 35 years (range 29-42), of which ten (28%) patients had family history (first grade) of breast cancer, four patients were BRCA 1 mutation carriers. Axillary node compromise was found in 19 patients (53.5%), 24 patients were stage II or III at diagnosis (68.5%), 22 (62.8%) were ER positive, and nine (25.7%) were HER-2 positive. In group A (n = 11), five patients diagnosed before 18th week decided that a therapeutic abortion be performed before treatment, two patients were treated during pregnancy, one with chemotherapy without treatment associated complications during delivery. Four women diagnosed after 28th week decided to delay the treatment until delivery. After a follow up of 172 months, the relapse free survival (RFS) was 69% at five years and 45% at ten years. Overall survival (OS) at five years was 90.8% and 74.2% at ten years for all patients. For group 'A' OS was higher with 90% at five years versus 80% in group 'B'. The differences between the groups were not statistically significant p = 0.368.\n\n\nCONCLUSIONS\nIn our experience, there is a higher OS in patients diagnosed during pregnancy suggesting a better prognosis for this group of women but the difference between the groups is not statistically significant. Our study is limited because of our small sample.",
"affiliations": "Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.;Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.;Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.;Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.;Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.;Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, Spain.",
"authors": "Blanquisett|Abraham Hernández|AH|;Vicent|Carmen Herrero|CH|;Gregori|Joaquín Gavilá|JG|;Zotano|Ángel Guerrero|ÁG|;Porta|Vicente Guillem|VG|;Simón|Amparo Ruiz|AR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2015.551",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2015.551can-9-551ResearchBreast cancer in pregnancy: an institutional experience Blanquisett Abraham Hernández Vicent Carmen Herrero Gregori Joaquín Gavilá Zotano Ángel Guerrero Porta Vicente Guillem Simón Amparo Ruiz Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia 46009, SpainCorrespondence to: Abraham Hernández Blanquisett. hernandezabraham86@gmail.com2015 08 7 2015 9 55118 2 2015 © the authors; licensee ecancermedicalscience.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nBreast cancer is one of the most common cancers diagnosed during pregnancy. Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within 12 months of delivery. Nowadays PABC can be safely diagnosed, staged, and treated during pregnancy with good outcomes for both the mother and the fetus. Recent studies suggest that prognosis of women diagnosed during postpartum seems to be worse. In order to gain a better understanding of the PABC, we reviewed our centre’s experience.\n\nPatients and methods\nWe assessed the clinicopathological parameters, evolution, and outcome of patients treated in the Fundación Instituto Valenciano de Oncología of Valencia, Spain, from October 1990 to October 2013, and compared the results of patients diagnosed during pregnancy (group ‘A’) and patients diagnosed within one year of delivery (group ‘B’).\n\nOf 12,000 cases of breast cancer registered in our database, 35 cases of PABC were identified. We included 11 patients in group ‘A’ and 24 in group ‘B’.\n\nResults\nIn our group the median age was 35 years (range 29–42), of which ten (28%) patients had family history (first grade) of breast cancer, four patients were BRCA 1 mutation carriers. Axillary node compromise was found in 19 patients (53.5%), 24 patients were stage II or III at diagnosis (68.5%), 22 (62.8%) were ER positive, and nine (25.7%) were HER-2 positive.\n\nIn group A (n = 11), five patients diagnosed before 18th week decided that a therapeutic abortion be performed before treatment, two patients were treated during pregnancy, one with chemotherapy without treatment associated complications during delivery. Four women diagnosed after 28th week decided to delay the treatment until delivery.\n\nAfter a follow up of 172 months, the relapse free survival (RFS) was 69% at five years and 45% at ten years. Overall survival (OS) at five years was 90.8% and 74.2% at ten years for all patients. For group ‘A’ OS was higher with 90% at five years versus 80% in group ‘B’. The differences between the groups were not statistically significant p = 0.368.\n\nConclusion\nIn our experience, there is a higher OS in patients diagnosed during pregnancy suggesting a better prognosis for this group of women but the difference between the groups is not statistically significant. Our study is limited because of our small sample.\n\npregnancybreast cancerpostpartumdelivery\n==== Body\nIntroduction\nBreast cancer is one of the most common cancers diagnosed during pregnancy along with melanoma and cervical cancer, with reported frequencies of one in 1000 to three in 10,000 pregnancies [1]. It is expected to become even more common, since these days women often delay childbearing to their 30s and 40s when breast cancer rates tend to increase [2]. However, the diagnosis of cancer during pregnancy is still an uncommon event.\n\nPABC has been traditionally associated with a worse prognosis and OS [3, 4, 5]. Most of women with PABC present larger tumours and have higher incidence of lymph node metastasis at diagnosis [6]. The reason might be because of a delay in diagnosis. This could be explained by engorgement and physiologic hypertrophy of the pregnant or lactating breast that creates difficulties in interpreting clinical examinations and mammography (increased breast density).\n\nUnfortunately, there is a knowledge gap for understanding whether pregnancy and other prognostic factors affect the survival of women with PABC.\n\nThe objective of this report is to analyse the clinicopathological characteristic and prognosis of patients diagnosed with PABC and compare the outcomes in women diagnosed during pregnancy with those diagnosed in the postpartum period, because the prognosis of this group seems to be more worse.\n\nPatients and method\nIn this descriptive study we assessed the clinicopathological parameters, evolution, treatment, and prognosis of patients with PABC and compared the results of patients diagnosed during pregnancy (group ‘A’) and patients diagnosed within one year of delivery (group ‘B’), treated in the Fundación Instituto Valenciano de Oncología (I.V.O) in Valencia, Spain.\n\nWe defined PABC as the breast cancer presented during pregnancy or up to one year after delivery. Of 12,000 cases of breast cancer registered in our database, we identified 35 cases of PABC. The histological grading was performed using the Scarff-Boom-Richardson (SBR) histological system. For the study of ER and PR a nuclear staining >1% of tumour cell was considered as positive. Patients were considered HER-2 positive if immunohistochemistry (IHC) was positive (+++) or HER-2 was amplified by FISH (Fluorescence in situ hybridisation). In our sample, we had three Patients with (++) for HER-2 IHC, and FISH was not performed to confirm their HER-2 status. We considered them as HER-2 negative for the analysis.\n\nWe recorded age at diagnosis, time from the beginning of the symptoms until diagnosis, tumour pathological findings, hormonal receptors, and HER-2 status, type of surgery, use of systemic therapy, and hormonal therapy. The characteristics of the patients are described in Table 1.\n\nOS was defined as the time period from initial diagnostic biopsy until death from any cause. RFS was defined as time period from diagnosis to first relapse (locoregional or systemic).\n\nWe also compared the outcome between patients diagnosed during pregnancy with those diagnosed after delivery. Data were analysed with SPSS 22.0 software. Survival curves were calculated according to the Kaplan-Meier analysis and compared with the log-rank test. A ‘p’ value <0.05 was considered statistically different.\n\nResults\nBaseline characteristics\nFrom October 1990 to October 2013, we found prevalence for PABC of 0.29%. The median age was 35 years (range 29–42). The median time between the first symptom and diagnosis was 5.2 months (range 0–15 months). Among them ten (28%) patients had first grade family history of breast cancer, mutational study for BRCA was performed in 12 patients, four were BRCA 1 mutation carriers, and five more patients had variants of uncertain significance (VUS) for BRCA 1 or BRCA 2.\n\nAxillary node compromise was found in 19 patients (53.5%), 24 patients (68.5%) were diagnosed in stage II or III, and three patients in stage IV.\n\nThe most common histological type was invasive ductal carcinoma found in 25 patients (71.4%), 11 were classified as grade 2, and eight as grade 3 according to SBR histological grading scale.\n\nThe status of oestrogenic and progesterone receptor was known in 32 patients (91%), of which 22 were ER positive (62.8%). The HER-2 status was studied in 29 (82%) patients. We found nine HER-2 positive (25.7%). We also found five triple-negative tumours.\n\nTreatments\nSurgery was performed in 87.7% of cases; total mastectomy (53.5%), partial mastectomy (34.2%). Among these 80% were treated with anthracycline and taxane-based chemotherapy. A total of 77% received local radiotherapy and 62.8% of patients received hormonal therapy, mostly with tamoxifen (86.3%).\n\nIn group A (n = 11), five patients diagnosed before 18th week decided that therapeutic abortion be performed before treatment, four patients diagnosed after 28th week decided to delay the treatment until delivery, and two patients were treated during pregnancy. One was treated with total mastectomy at 28th week without complications.\n\nThe other woman with a twin pregnancy was diagnosed in the 12th week of gestation; she decided to start treatment, total mastectomy was performed at 13th week of gestation without complications. Adjuvant treatment with doxorubicin and cyclophosphamide was started at 21th week of gestation with nausea and vomiting grade 1 as only side effect. After the third cycle she had grade 4 toxicity (neutropaenia and mucositis). We decided to stop adjuvant treatment at 24th week of gestation, the ultrasound revealed an appropriate weight for the gestational age at this moment. A planned cesarean delivery was performed at 32th week of gestation because of intrauterine growth restriction diagnosed in the ultrasound scan. The twins were born with low weight (1200 g and 1400 g) with an Apgar score of 7/10 and 10/10; one of them had to be taken to the intensive care unit for a few days for a respiratory infection. After two years of follow up, the girls had a normal weight for her age (75th percentile), at last follow-up (12 years) they had not shown any complication associated with chemotherapy treatment.\n\nIn group B (n = 24), 21 women were treated by surgery, 50% with total mastectomy, and 37.5% with partial surgery. A total of 20 received chemotherapy and 17 hormonal therapies.\n\nEfficacy results\nThe median follow-up was 172 months for the total group. At last follow-up 11 patients had relapsed (31.4%). The RFS was 69% at five years and 45% at ten years of follow-up, with a median of 32 months. The difference between the groups was not statistically significant.\n\nFive patients (14.2%) had died and all of them because of breast cancer. OS at five years was 90.8% and 74.2% at ten years for all patients. For group ‘A’ OS was higher with 90% at five years versus 80% in group ‘B’, but the differences between the groups were not statistically significant (p = 0.368). (Figure 1).\n\nLower OS at five years was associated with patients with axillary node compromise at diagnosis (Figure 2). OS at five years was 100% for patients with cN0; 91% for cN1 patients, and 0% for cN2 with p = 0.002. The differences can be explained because we only included four patients in cN2.\n\nDiscussion\nBreast cancer occurring during pregnancy or within first year after delivery is considered to be PABC. PABC is relatively rare and its incidence is 0.2–3.8% [7]. In our study PABC constitutes 0.29% of total cases of breast cancer patients.\n\nThe frequency of PABC is increasing. In recent data published by Beadle et al, in young breast cancer patients, out of 668 patients analysed, 104 were PABC which constitute up to 15% of cases [8]. This study was made in a tertiary centre for referral of pregnant patients and that can explain their high frequency of cases. However, the delay in the age at first pregnancy could explain why the frequency on PABC has increased, mainly in developed countries.\n\nThe median age of diagnosis for our patients was 35 years (range: 29–42 years) similar age was reported by Sanchez et al [9]. In previous studies, PABC was associated with a genetic predisposition and a strong family history [10, 11]. We found that 28% of our patients had a positive family history and four patients were BRCA 1 mutation carriers, and five more patients had variants of uncertain significance (VUS) for BRCA 1 or BRCA 2.\n\nThe diagnosis of PABC may be difficult because the anatomic changes of the breast. Mostly of women who are diagnosed in locally advanced stages (68% in our database), with poorly differentiated tumours, are often ER negative [1, 3]. The delay in diagnosis is probably explained by the difficulties in the physical examination and the general assumption that a tumour in breast is benign and possibly related to pregnancy. In a recent study published by Gogia et al the median duration of symptoms and diagnosis was 11.5 months [12]. Our median duration between the first symptom and diagnosis was 5.2 months (range 0–15 months).\n\nNumerous studies have found that PABC was associated with larger tumours and positive axillary nodes, from 56% to 83% of pregnant women at diagnosis versus 38% to 54% in non-pregnant population [13, 15]. In our study axillary node compromise was found in 53.5% of the cases. In contrast to earlier studies, in this report we found higher ER/PR expression (62.8%) and lower HER-2/neu overexpression (25.7%) [13, 16, 17].\n\nTreatment of the disease during pregnancy with surgery and chemotherapy is effective and feasible. The use of chemotherapy after the first trimester has been widely reported based on schemes such as anthracyclines and taxanes [1, 4], which has been used in our patient.\n\nThe decision to terminate a pregnancy during breast cancer is a highly personal decision to be made by an informed woman. A woman may be advised to terminate a pregnancy if it is felt that her life expectancy may not be longer than gestation. More recently the frequency of the recommendation for termination has been decreasing, regarding the similar prognosis for the pregnant patient, and the safety of surgery and chemotherapy during pregnancy [1]. In addition, termination of the pregnancy has not been shown to improve survival. In our study, five patients diagnosed before 18th week decided that therapeutic abortion was performed before treatment. We treated two patients during pregnancy with good outcomes for the mothers and the newborns.\n\nPABC has traditionally been associated with a worse prognosis and OS [3, 4, 5]. Azim et al reported in their metaanalysis of PABC that there was a poorer breast cancer outcome for women diagnosed in the postpartum period compared with those diagnosed with breast cancer during pregnancy [5]. Amant et al analysed the prognosis of 311 women with breast cancer, who were diagnosed and treated during pregnancy. Patients diagnosed with breast cancer postpartum were excluded from this analysis. Interestingly, no differences in mortality were found between this group and a cohort of the same age with breast cancer unrelated to pregnancy [18]. These findings suggest that pregnancy has no negative impact on breast cancer giving relevant information for counselling women who are diagnosed during pregnancy [19].\n\nHowever, the same conclusion is not extended for patients with breast cancer diagnosed in the postpartum period. In this situation, the prognosis seems to be more worse [20, 21]. Many studies in the past have considered the two groups (breast cancer during pregnancy and postpartum breast cancer) as part of the same condition, and this could be the reason for the controversial results on prognosis [22].\n\nIn our study, we reported a RFS of 69% and 45% at five and ten years with a median of 32 months and we estimated an OS of 90% and 74% at five and ten years. Prognosis in patients with breast cancer diagnosed in the postpartum period seems to be more worse [20, 2]. We included both populations; breast cancer diagnosed during pregnancy (group ‘A’) and after 1st year of delivery (group ‘B’). Interestingly, for group ‘A’ OS was higher with 90% at five years versus 80% in group ‘B’, but the difference found between the groups was not statistically significant. The limitations of our study are mainly based on the retrospective nature of the data and the small sample size.\n\nConclusions\nNowadays PABC can be safely diagnosed, staged, and treated during pregnancy with good outcomes. We have successfully treated two patients during pregnancy, and those patients did not present any complications associated with treatments during delivery and their children are growing up healthy.\n\nIn our experience, there is a higher OS in patients diagnosed during pregnancy suggesting a better prognosis for this group of women. The difference found between the groups was not statistically significant. Our study is limited by the small number of patients and we cannot make further conclusions.\n\nWe need more translational studies for a better understanding of PABC biology leading to a better classification of groups of poor prognosis.\n\nWe conclude that once a pregnant woman is diagnosed with breast cancer she should be referred to receive a multidisciplinary approach and personalised treatments looking for the best outcomes for both the mother and the fetus.\n\nFigure 1. OS for groups.\nFigure 2. OS axillary node compromise.\nTable 1. Patients’ characteristics.\nPatients’ and disease characteristics\tGroup A (n = 11)\tGroup B (n = 24)\tTotal (n = 35)\t\ncT 2-3-4\t8\t18\t26\t\ncN 0\t6\t10\t16\t\ncN 1-2\t5\t14\t19\t\nStage II–III\t7\t17\t24\t\nStage IV\t0\t3\t3\t\nCDI\t8\t17\t25\t\nGrade 2\t3\t8\t11\t\nGrade 3\t3\t5\t8\t\nER/RP positive\t5\t17\t22\t\nHER-2 positive\t1\t8\t9\t\nPartial mastectomy\t3\t9\t12\t\nTotal mastectomy\t7\t12\t19\t\nAnthracycline and taxane\t8\t20\t28\t\nRelapse\t3\t8\t11\t\nExitus\t1\t4\t5\n==== Refs\nReferences\n1. Litton JK Theriault RL Breast cancer and pregnancy: current concepts in diagnosis and treatment Oncologist 2010 15 12 1238 47 10.1634/theoncologist.2010-0262 21147871 \n2. Pavlidis N Pentheroudakis G The pregnant mother with breast cancer: diagnostic and therapeutic management Cancer Treat Rev 2005 31 6 439 47 10.1016/j.ctrv.2005.04.010 15946802 \n3. Peccatori F Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2013 Suppl 6 160 70 23813932 \n4. Amant F Breast cancer in pregnancy Lancet 2012 379 9815 570 9 10.1016/S0140-6736(11)61092-1 22325662 \n5. Azim H Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies Cancer Treat Rev 2012 38 7 834 42 10.1016/j.ctrv.2012.06.004 22785217 \n6. Ishida T Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: Analysis of case-control study in Japan Jpn J Cancer Res 1992 83 11 1143 9 10.1111/j.1349-7006.1992.tb02737.x 1483929 \n7. Wallack MK Gestational carcinoma of the female breast Curr Probl Cancer 1983 7 9 1 58 10.1016/S0147-0272(83)80006-3 6303698 \n8. Beadle BM The impact of pregnancy on breast cancer outcomes in women < or = 35 years Cancer 2009 115 6 1174 84 10.1002/cncr.24165 19204903 \n9. Sánchez C Breast cancer and pregnancy: a comparative analysis of a Chilean cohort Ecancermedicalscine 2014 8 434 10.3332/ecancer.2014.434 \n10. Shen T High frequency of allelic loss of BRCA2 gene in pregnancy-associated breast carcinoma J Natl Cancer Inst 1999 91 19 1686 7 10.1093/jnci/91.19.1686 10511599 \n11. Johannsson O Pregnancy-associated breast cancer in BRCA1 and BRCA2 germline mutation carriers Lancet 1998 352 9137 1359 60 10.1016/S0140-6736(05)60750-7 9802282 \n12. Gogia A Pregnancy associated breast cancer: An institutional experience Indian J Cancer 2014 51 2 167 9 10.4103/0019-509X.138285 25104202 \n13. Middleton LP Breast carcinoma in pregnant women: Assessment of clinicopathologic and immunohistochemical features Cancer 2003 98 5 1055 60 10.1002/cncr.11614 12942575 \n14. Garcia Manero M Cancer de mama durante el embarazo Rev Med Univ Navarra 2008 52 1 18 24 18578193 \n15. Woo JC Breast cancer in pregnancy. A literature review Arch Surg 2003 138 1 91 8 10.1001/archsurg.138.1.91 12511159 \n16. Azim H Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study J Clin Oncol 2013 31 1 73 9 10.1200/JCO.2012.44.2285 23169515 \n17. Elledge RM Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients Cancer 1993 71 8 2499 506 8095853 \n18. Amant F Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study J Clin Oncol 2013 31 20 2532 9 10.1200/JCO.2012.45.6335 23610117 \n19. Theriault RL Litton JK Pregnancy during or after breast cancer diagnosis: what do we know and what do we need to know? J Clin Oncol 2013 31 20 2521 2 10.1200/JCO.2013.49.7347 23733755 \n20. Callihan EB Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy associated breast cancer Breast Cancer Res Treat 2013 138 2 549 59 10.1007/s10549-013-2437-x 23430224 \n21. Johansson AL Stage at diagnosis and mortality in women with pregnancy-associated breast cancer (PABC) Breast Cancer Res Treat 2013 139 1 183 92 10.1007/s10549-013-2522-1 23576078 \n22. Tuesca A Locoregional treatment of breast cancer during pregnancy Gynecol Surc 2014 11 4 279 84 10.1007/s10397-014-0860-6\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "9()",
"journal": "Ecancermedicalscience",
"keywords": "breast cancer; delivery; postpartum; pregnancy",
"medline_ta": "Ecancermedicalscience",
"mesh_terms": null,
"nlm_unique_id": "101392236",
"other_id": null,
"pages": "551",
"pmc": null,
"pmid": "26284115",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "10511599;22325662;23610117;19204903;22785217;23733755;18578193;23169515;6303698;8095853;24944576;12942575;23430224;23576078;25419205;12511159;23813932;15946802;9802282;21147871;1483929;25104202",
"title": "Breast cancer in pregnancy: an institutional experience.",
"title_normalized": "breast cancer in pregnancy an institutional experience"
} | [
{
"companynumb": "ES-ROXANE LABORATORIES, INC.-2015-RO-01703RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"dru... |
{
"abstract": "A 57-year-old man was admitted for 1 month of accelerating hemoptysis and hematemesis. Two weeks earlier, he first presented with fevers and hemoptysis of 2 weeks' duration and was diagnosed with community-acquired pneumonia treated with 5 days of ceftriaxone and azithromycin. He improved and was discharged, but his hemoptysis recurred 1 day after discharge and progressed over 9 days, leading to the present admission. He endorsed an 5-kg weight loss, daily fevers up to 39.4°C, and night sweats since discharge. His medical history was significant for peptic ulcer disease complicated by a perforated gastric ulcer 30 years ago, type 2 diabetes, and Barrett esophagus with recent normal upper endoscopy. The patient had coarctation of the aorta repaired 35 years ago. The patient takes aspirin, atorvastatin, and pantoprazole. He emigrated from Mexico 10 years before presentation and lives in Texas with his family. He returns to Mexico several times per year, most recently 2 days before admission. He works at a supermarket. He does not smoke, drink, or use illicit drugs. He denied sick contacts, pets, or incarceration.",
"affiliations": "Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.;Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.;Department of Medicine, Oregon Health Sciences University, Portland, OR.;Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: Jason.Clark@UTSouthwestern.edu.",
"authors": "Sumarsono|Andrew|A|;Brown|Timothy J|TJ|;Atkin|Stan D|SD|;Clark|Jason|J|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2018.07.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "154(6)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001013:Aorta, Thoracic; D001017:Aortic Coarctation; D001807:Blood Vessel Prosthesis; D001983:Bronchial Fistula; D000072226:Computed Tomography Angiography; D003937:Diagnosis, Differential; D018450:Disease Progression; D005334:Fever; D006396:Hematemesis; D006469:Hemoptysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D016459:Prosthesis-Related Infections; D012086:Reoperation; D016896:Treatment Outcome; D016157:Vascular Fistula; D058017:Vascular Grafting",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e181-e185",
"pmc": null,
"pmid": "30526987",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 57-Year-Old Man With Subacute Progressive Hemoptysis and Fevers.",
"title_normalized": "a 57 year old man with subacute progressive hemoptysis and fevers"
} | [
{
"companynumb": "US-BAYER-2018-231695",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Gemcitabine and docetaxel combination chemotherapy is the standard of care for patients with unresectable recurrent or metastatic leiomyosarcoma of the uterus. Although they are generally well-tolerated agents, they can also cause severe and life-threatening pulmonary toxicities. Here, we describe a case of grade 4 pneumonitis due to gemcitabine and docetaxel in a 74-year-old woman with recurrent, metastatic uterine leiomyosarcoma. Despite early recognition of chemotherapy-induced lung injury and early administration of corticosteroid, she developed noncardiogenic pulmonary edema, diffuse alveolar hemorrhage, and acute respiratory distress syndrome. She required multiple intubations and a tracheostomy. Physicians should not only be aware of gemcitabine and docetaxel's potential to cause life-threatening pulmonary injuries but also recognize the variability in clinical presentations and treatment responses, the radiographic findings of these lung toxicities, and the need for early corticosteroid therapy in these cases.",
"affiliations": "Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.;Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.;Department of Radiology, University of Wisconsin School of Medicine and Public Health, WI 53792, USA.;Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.",
"authors": "Wang|Connor|C|https://orcid.org/0000-0001-6856-4273;Rose|Stephen|S|https://orcid.org/0000-0001-8354-6751;Mankowski Gettle|Lori|L|;Spencer|Ryan|R|https://orcid.org/0000-0002-2492-9063",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/4629452",
"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi 10.1155/2020/4629452Case ReportGrade 4 Pneumonitis in a Patient Treated with a Combination of Gemcitabine and Docetaxel for Recurrent Leiomyosarcoma of the Uterus https://orcid.org/0000-0001-6856-4273Wang Connor \n1\nhttps://orcid.org/0000-0001-8354-6751Rose Stephen \n2\nMankowski Gettle Lori \n3\nhttps://orcid.org/0000-0002-2492-9063Spencer Ryan rjspencer2@wisc.edu\n2\n\n1Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA\n2Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA\n3Department of Radiology, University of Wisconsin School of Medicine and Public Health, WI 53792, USAAcademic Editor: Kyousuke Takeuchi\n\n2020 7 2 2020 2020 462945221 11 2019 31 1 2020 Copyright © 2020 Connor Wang et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Gemcitabine and docetaxel combination chemotherapy is the standard of care for patients with unresectable recurrent or metastatic leiomyosarcoma of the uterus. Although they are generally well-tolerated agents, they can also cause severe and life-threatening pulmonary toxicities. Here, we describe a case of grade 4 pneumonitis due to gemcitabine and docetaxel in a 74-year-old woman with recurrent, metastatic uterine leiomyosarcoma. Despite early recognition of chemotherapy-induced lung injury and early administration of corticosteroid, she developed noncardiogenic pulmonary edema, diffuse alveolar hemorrhage, and acute respiratory distress syndrome. She required multiple intubations and a tracheostomy. Physicians should not only be aware of gemcitabine and docetaxel's potential to cause life-threatening pulmonary injuries but also recognize the variability in clinical presentations and treatment responses, the radiographic findings of these lung toxicities, and the need for early corticosteroid therapy in these cases.\n\nSchool of Medicine and Public Health, University of Wisconsin-Madison\n==== Body\n1. Introduction\nUterine leiomyosarcoma (uLMS) is the most common uterine sarcoma. It has an annual incidence of approximately 0.8 per 100,000 women with over 60% diagnosed at International Federation of Gynecology and Obstetrics (FIGO) stage I [1]. Although the majority are limited to the uterus on presentation, these tumors are highly aggressive and have a high recurrence rate. Initial treatment for early-stage disease is total hysterectomy (TH) with or without bilateral salpingo-oophorectomy (BSO) and lymphadenectomy depending on patient factors and the clinical scenario. For stage I patients, it is reasonable to consider either observation or adjuvant chemotherapy. Gynecologic Oncology Group- (GOG-) 0277 attempted to investigate the role of adjuvant chemotherapy for uLMS; however, this trial did not complete its targeted accrual, precluding comparison of survival outcomes in completely resected uLMS [2]. Additional prospective and retrospective data have shown observation with imaging to be equivalent to adjuvant chemotherapy [3].\n\nIn the recurrent/metastatic settings, multiple studies have demonstrated the efficacy and tolerability of gemcitabine/docetaxel (G/D) for uLMS. Notably, GOG-87L [4] and GOG-131G [5] demonstrated G/D as an active regimen for chemotherapy-naïve and for second-line treatment of advanced, unresectable uLMS, respectively. Further, GOG-250 [6] investigated the addition of bevacizumab in the treatment of chemotherapy-naïve, metastatic uLMS. This study closed for futility after demonstrating that bevacizumab did not improve outcomes. G/D remains the standard of care in this setting.\n\nGemcitabine (a pyrimidine analog) and docetaxel (a taxane antineoplastic agent) are used in a variety of solid tumors. Myelosuppression is the most common dose-limiting side effect for both agents [4, 5, 7]. Up to 25% of patients receiving gemcitabine may report adverse pulmonary symptoms, but these are generally grade I-II pulmonary toxicities that manifest as dyspnea but do not limit self-care [7]. Severe adverse pulmonary events, defined as ≥grade 3 by the National Cancer Institute for Common Terminology Criteria for Adverse Events (CTCAE), have been described in case reports or studies with both gemcitabine and docetaxel independently, as well as in combination. Here, we report a case of grade 4 pneumonitis after G/D combination therapy in a patient with recurrent uLMS. To our knowledge, this is the first reported case of such a severe pulmonary toxicity in a patient receiving G/D for recurrent uLMS.\n\n2. Case Presentation\nThis case is of a 74-year-old Caucasian woman who was initially diagnosed with stage IB uLMS in May 2018 after she underwent an exploratory laparotomy, TH, and BSO. Intraoperative frozen pathology was notable for spindle cell neoplasm—unable to further characterize. The final pathology revealed uLMS (31 × 29 × 16 cm in size) confined to the uterus. Her past medical history included hypertension and hypothyroidism without significant cardiopulmonary history. She never received radiation to her thorax and never smoked. She opted for observation instead of adjuvant therapy following her surgery. Twelve months later, in May of 2019, a surveillance computed tomographic (CT) scan showed mesenteric and peritoneal masses without thoracic involvement. Her subsequent percutaneous biopsy demonstrated recurrent uLMS. She was started on intravenous (IV) gemcitabine 900 mg/m2 on cycle days 1 and 8 and IV docetaxel 100 mg/m2 on cycle day 8 every 21 days. Her chemotherapy course was complicated by neutropenia, requiring a dose reduction in docetaxel to 75 mg/m2 starting on cycle 3 day 8.\n\nOn day 19 of cycle 4 of G/D (eighty-two days after chemotherapy initiation), she presented to the emergency department (ED) with 1 week of cough and dyspnea at rest that interfered with her activities of daily living. Her review of systems was otherwise unremarkable. On physical exam, she was afebrile and had a pulse of 81 beats per minute (bpm), blood pressure of 95/56 mmHg, respiratory rate of 22 breaths per minute, and oxygen saturation (SaO2) of 88%. During her time in the ED, she had an escalating oxygen (O2) requirement necessitating up to 6 L/min via a nasal cannula. Her cardiac exam was normal. Her pulmonary exam demonstrated diminished breath sounds and crackles throughout her mid and lower lungs bilaterally. Her abdominal exam was normal. Her extremities showed trace nonpitting bilateral lower extremity edema.\n\nLaboratory studies were significant for leukocytosis (18.2 K/μL with 730 cells/μL of immature granulocytes and an absolute neutrophil count of 13,650 cells/μL). Her white blood cell count 4 days prior was 4.8 K/μL. Her creatinine was 0.87 mg/dL (previously 0.69 mg/dL), and she was hyponatremic (129 mmol/L) and hypokalemic (2.7 mmol/L). She initially had a slight troponin leak that peaked at 0.05 ng/mL and a BNP of 206 pg/mL. An EKG showed no acute pathology. CT pulmonary angiography showed no evidence of pulmonary embolism but new extensive peribronchial vascular ground glass opacities and internal and interlobular septal thickening (Figure 1). Given her clinical symptoms, laboratory values, and imaging findings, she was admitted for treatment of community-acquired pneumonia. IV ceftriaxone and oral azithromycin were initiated, and an infectious workup was begun. This included a urinalysis with reflex urine culture, a urine antigen study, a sputum culture, a nasal methicillin-resistant Staphylococcus aureus (MRSA) test, and a viral respiratory panel that tested for influenza, parainfluenza, rhinovirus, metapneumovirus, respiratory syncytial virus, and adenovirus. Blood cultures were obtained when she became febrile on Hospital Day 2 (HD#2).\n\nOn HD#2, she continued to have increasing O2 requirements with desaturations to mid-80% SaO2 on pulse oximetry. Chest X-ray (CXR) revealed worsening airspace opacities. She was started on continuous positive airway pressure after a trial of a high-flow nasal cannula. Her symptoms did not improve. On HD#3, the intensive care unit (ICU) service was consulted, and she was transferred to the ICU for respiratory failure in the setting of likely noncardiogenic pulmonary edema (NCPE) and cryptogenic organizing pneumonia. A repeat CXR four hours later showed increased opacities in her right basilar lung. Her empiric antibiotic regimen was broadened to IV cefepime. Hydrocortisone 50 mg every 6 hours and IV furosemide were additionally begun.\n\nIn the ICU on HD#4, she transitioned to bilevel positive airway pressure ventilation. She remained tachypneic with respiratory rates over 30 breaths per minute and hypoxic receiving fraction of inspired oxygen (FiO2) at 90%. An arterial blood gas revealed a pH of 7.32, partial pressure of oxygen (PaO2) of 62 mmHg, partial pressure of carbon dioxide of 39 mmHg, and bicarbonate of 19.6 mmol/L. Her anion gap was normal, consistent with a primary metabolic acidosis with respiratory compensation. Additionally, given her arterial hypoxemia with a PaO2/FiO2 ratio of 68.89 mmHg, acutely worsening respiratory symptoms, bilateral pulmonary opacities on CXR and CT, and absence of left heart failure on echocardiogram, she met diagnostic criteria for acute respiratory distress syndrome (ARDS). Her hydrocortisone was increased to 100 mg every 6 hours, sulfamethoxazole/trimethoprim and azithromycin were initiated for coverage of atypical pneumonia, and diuresis was continued for NCPE/ARDS.\n\nShe was ultimately intubated on HD#5. Bronchoscopy with bronchoalveolar lavage (BAL) was performed to assist with elucidating an etiology. BAL cytology was notable for a neutrophilic predominance with serial bloody aliquots suggestive of diffuse alveolar hemorrhage (DAH). Further workup using BAL cytology included testing for fungus (Histoplasma species, Aspergillus species, Candida species, and fungal culture), bacteria (Pneumocystis jirovecii, Pseudomonas aeruginosa, MRSA, Nocardia species, Legionella species, Mycobacterium species, and bacterial culture), and vasculitides (autoimmune-mediated, immune complex-mediated, and antineutrophil cytoplasmic antibody-associated). These all returned negative. Given all of these results and input from the multiple clinical services involved in her care, her condition was attributed to grade 4 pneumonitis from G/D. She remained on her steroid regimen to treat her G/D-induced pneumonitis, and her empiric antibiotics were discontinued when the bacterial studies resulted.\n\nOn HD#7, she was extubated to a high-flow nasal cannula at 40 L/min of oxygen and slowly transitioned to a face mask on 3 L/min of oxygen over seven days. A repeat chest CT on HD#13, ten days after starting steroid therapy, revealed worsening ground glass airspace opacities (Figure 2). An extended steroid taper was initiated and diuresis continued. Her diet was advanced to clear liquids, which she tolerated initially.\n\nOn HD#16, she had an acute hypoxemic event requiring an emergent intubation and was transferred back to the ICU. Repeat chest CT on HD#17 showed worsening lung injury (Figure 3). She was extubated on HD#18 but required subsequent reintubation. Her steroid regimen was escalated to methylprednisolone 60 mg IV twice daily. On HD#22, given her worsening hypoxemic respiratory failure, multiple failed extubations, and difficulty weaning her from ventilatory support, a tracheostomy was performed. On HD#24, she was tolerating intermittent tracheostomy mask alternating with pressure-regulated volume control for rest periods. She was discharged to a long-term acute care hospital (LTACH), where she stayed for approximately 3 weeks and was weaned from mechanical ventilation and had her tracheostomy decannulated. At the time of discharge from the LTACH, she was saturating consistently at or above 95% on room air and tolerating a general diet. She was transferred to inpatient rehabilitation where she stayed for 2 weeks for comprehensive rehabilitation. Repeat chest CT 5 weeks after discharge demonstrated improved bilateral ground glass and reticular opacities. There were no findings of intrathoracic metastatic disease (Figure 4). At her 6-week posthospitalization follow-up, her Eastern Cooperative Oncology Group performance status was grade 2.\n\n3. Discussion\nOur case illustrates a rare occurrence of G/D-associated grade 4 pneumonitis presenting with rapidly progressing pulmonary failure in a patient with recurrent uLMS. In general, these pulmonary side effects can be variable in clinical presentation, severity, time from chemotherapy initiation, and clinical response to appropriate therapy for lung injury. They can manifest as mild to severe dyspnea, NCPE, DAH, ARDS, and interstitial pneumonitis (IP) [7–12]. Our patient, despite appropriate treatment with early steroid therapy, declined clinically and radiographically. Boiselle et al. [9] described the common CT imaging features in three patients with gemcitabine-induced lung injury. The predominant CT finding was ground glass attenuation accompanied by thickened septal lines and reticular opacities. None had suggestions of cardiogenic pulmonary edema [7, 9]. This pattern was consistent with the findings in our patient's CT scans (Figures 1–3) throughout her hospitalization.\n\nThe mechanism for gemcitabine-induced pulmonary toxicity is unknown, but it is thought to be due to drug-related increased capillary permeability leading to cytokine-mediated inflammatory responses [7, 8]. As a result, pulmonary toxicities associated with gemcitabine use can range from mild bronchospasms with dyspnea that self-resolve or resolve quickly with steroids to fatal injuries, including NCPE, interstitial pulmonary damage, alveolar wall inflammation and scarring, alveolar hemorrhage, and ARDS [7–10]. The mechanism of lung injury caused by gemcitabine is similar to the proposed method by which taxanes and docetaxel lead to pulmonary toxicity. Docetaxel is known to cause fluid accumulation in peripheral tissues, pleura, or peritoneum via capillary leakage, which induces a hypersensitivity reaction. This syndrome worsens with increased cycles of docetaxel, and premedication with steroids can decrease this response. Though docetaxel-induced pneumonitis has not been well described [11, 13], coadministration with gemcitabine may potentiate pulmonary inflammation and toxicity.\n\nRisk factors for pulmonary toxicities have been hypothesized and include thoracic metastases, smoking history, prior or concurrent radiation therapy, and the use of multiagent therapy (including the G/D combination) [7]. In our patient, her only known risk factor was receipt of combination chemotherapy. Her pulmonary toxicity was likely due to G/D potentiating and augmenting cytokine release and the resultant lung damage.\n\nWithin the literature, there is a paucity of case reports on this chemotherapy combination and its associated adverse pulmonary events. One case report described a patient who developed likely grade 3 pulmonary toxicity while receiving G/D for metastatic primary ovarian LMS. She completely improved with steroid therapy and continued to receive the same chemotherapy regimen with a partial cancer response [12]. In a report of three patients with metastatic urothelial carcinoma treated with G/D, two had at least grade 3 pulmonary toxicity. One of those two patients died from respiratory failure with post mortem examination revealing changes consistent with DAH, and the other responded to high-dose steroids and recovered [13].\n\nAlthough not detailed in case reports, studies investigating the use of G/D for uLMS have reported pulmonary toxicities as well. However, whether these instances were directly related to G/D is unknown. In a phase II trial of 34 patients with unresectable uLMS treated with G/D, 7 had at least grade 3 dyspnea [14]. In the arm of GOG-277 in which patients received gemcitabine plus docetaxel followed by doxorubicin for early-stage uLMS, grade 3 dyspnea was seen in 1 of the 17 patients [2]. GOG-87L [4], which trialed G/D in 39 women with advanced, unresectable uLMS without prior cytotoxic chemotherapy exposure, reported one grade 4 hypoxia and no additional grade 3 events. In that study, the patient had pulmonary metastases and previous thoracic radiation. Although she improved after treatment for possible Pneumocystis jirovecii pneumonia, she was removed from the study for possible G/D-related pulmonary toxicity. In GOG-131G [5], the investigators enrolled 48 metastatic uLMS patients who experienced cancer progression after one prior cytotoxic chemotherapy regimen. They had four grade 3 or worse pulmonary toxicities; however, none had clinical or radiographic evidence of G/D-induced pneumonitis, as their patients had attributable causes to their pulmonary toxicities, which included pneumonia with and without hypoxia, bilateral pleural effusion, and acute dyspnea and hypoxia during chemotherapy infusion. Similarly, in a study using G/D for advanced or recurrent uLMS and undifferentiated endometrial sarcoma in Japan, none of their 8 uLMS patients experienced pulmonary toxicity [15].\n\nSevere lung toxicity due to chemotherapeutic agents is a diagnosis of exclusion. Workup should include tests and radiographs to exclude infectious, cardiogenic, vascular, oncologic, and drug-induced etiologies. In our patient and in several cases described in the literature, the initial treatment steps should include supportive therapy with nebulizers and supplemental oxygen, discontinuation of chemotherapeutic agents, and early steroid administration [8–11, 13]. The literature reports a range of clinical response to these interventions. Treatment response ranged from significant improvement with resolution of pulmonary toxicity to rapid progression and to respiratory failure and death [8–13]. Fenocchio et al. described a case of pancreatic adenocarcinoma treated with gemcitabine where the patient developed severe gemcitabine-induced pulmonary toxicity refractory to steroids and other conventional treatments. However, the patient responded completely to imatinib mesylate, a tyrosine-kinase inhibitor with antineoplastic activity. Imatinib mesylate has been studied as a potential treatment for lung fibrosis and may demonstrate a role in reversing gemcitabine-induced lung injury, but more studies are required before recommending widespread use [16]. Our patient was treated with high-dose steroid therapy early, starting on HD#3. This was increased once a diagnosis of chemotherapy-associated pneumonitis was made. Unfortunately, even though she received the appropriate interventions, her symptoms developed and progressed rapidly over her hospital course, which culminated in multiple intubations and ultimately a tracheostomy.\n\nIn the case of recurrent uLMS, the standard of care is G/D combination therapy. However, they are both widely used and generally well-tolerated chemotherapy agents [2–6]; prescribers should be cognizant of this rare, life-threatening pulmonary toxicity that we describe for the first time in a patient with recurrent, metastatic uLMS.\n\nAcknowledgments\nThis research was supported by the Department of Obstetrics and Gynecology at the University of Wisconsin School of Medicine and Public Health.\n\nConflicts of Interest\nThe authors indicated no potential conflicts of interest or financial disclosures.\n\nAuthors' Contributions\nAll authors have read and approved the manuscript.\n\nFigure 1 Imaging on presentation to ED. (a) CXR with multifocal airspace opacities. (b–d) CT scan of the lungs at upper (b), mid (c), and base (d) illustrating bilateral peribronchial consolidation and ground glass opacities.\n\nFigure 2 Imaging on HD#13. (a) CXR with continued bibasilar opacities and edema. No effusion. (b–d) CT scan of the lungs at upper (b), mid (c), and base (d) illustrating increased severity of ground glass airspace opacities.\n\nFigure 3 Imaging on HD#16 after an acute hypoxic event. (a) CXR with a new endotracheal tube and persistent diffuse lung disease. (b–d) CT scan of the lungs at upper (b), mid (c), and base (d) illustrating continued peribronchial consolidation and decreased ground glass opacities. An endotracheal tube can be seen in the trachea.\n\nFigure 4 Imaging on 48 days after a discharge CT scan of the lungs at upper (a), mid (b), and base (c) illustrating improved residual ground glass and reticular opacities bilaterally.\n==== Refs\n1 Roberts M. E. Aynardi J. T. Chu C. S. Uterine leiomyosarcoma: a review of the literature and update on management options Gynecologic Oncology 2018 151 3 562 572 10.1016/j.ygyno.2018.09.010 2-s2.0-85053731773 30244960 \n2 Hensley M. L. Enserro D. Hatcher H. Adjuvant gemcitabine plus docetaxel followed by doxorubicin versus observation for high-grade uterine leiomyosarcoma: a phase III NRG Oncology/Gynecologic Oncology Group Study Journal of Clinical Oncology 2018 36 33 3324 3330 10.1200/JCO.18.00454 2-s2.0-85056783564 \n3 Littell R. D. Tucker L. Y. Raine-Bennett T. Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: trends and survival outcomes Gynecologic Oncology 2017 147 1 11 17 10.1016/j.ygyno.2017.07.122 2-s2.0-85025476209 28747255 \n4 Hensley M. L. Blessing J. A. Mannel R. Rose P. G. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial Gynecologic Oncology 2008 109 3 329 334 10.1016/j.ygyno.2008.03.010 2-s2.0-44449096592 18534250 \n5 Hensley M. L. Blessing J. A. Degeest K. Abulafia O. Rose P. G. Homesley H. D. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study Gynecologic Oncology 2008 109 3 323 328 10.1016/j.ygyno.2008.02.024 2-s2.0-44449135941 18394689 \n6 Hensley M. L. Miller A. O'Malley D. M. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study Journal of Clinical Oncology 2015 33 10 1180 1185 10.1200/JCO.2014.58.3781 2-s2.0-84927644800 25713428 \n7 Belknap S. M. Kuzel T. M. Yarnold P. R. Clinical features and correlates of gemcitabine-associated lung injury: findings from the RADAR project Cancer 2006 106 9 2051 2057 10.1002/cncr.21808 2-s2.0-33646353444 16568459 \n8 Ko E. Lee S. Goodman A. Gemcitabine pulmonary toxicity in ovarian cancer The Oncologist 2008 13 7 807 811 10.1634/theoncologist.2008-0049 2-s2.0-48749087387 18614588 \n9 Boiselle P. M. Morrin M. M. Huberman M. S. Gemcitabine pulmonary toxicity: CT features Journal of Computer Assisted Tomography 2000 24 6 977 980 10.1097/00004728-200011000-00027 2-s2.0-0034466211 11105721 \n10 Baig J. Shokouh-amiri M. Chan J. Chowdhery R. Danthurthy S. Venepalli N. K. The spectrum of pulmonary toxicity in pancreatic cancer patients receiving gemcitabine combination chemotherapy Case Reports in Oncology 2019 12 2 506 512 10.1159/000500242 2-s2.0-85068593081 31341464 \n11 Yumuk P. F. Kefeli U. Ceyhan B. Pulmonary toxicity in patients receiving docetaxel chemotherapy Medical Oncology 2010 27 4 1381 1388 10.1007/s12032-009-9391-9 2-s2.0-79951774989 20035385 \n12 Furutake Y. Fukagawa T. Suga Y. Gemcitabine and docetaxel in a patient with primary ovarian leiomyosarcoma: a case report and review of literature International Cancer Conference Journal 2018 7 1 11 15 10.1007/s13691-017-0309-7 31149505 \n13 Dunsford M. L. Mead G. M. Bateman A. C. Cook T. Tung K. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma Annals of Oncology 1999 10 8 943 947 10.1023/a:1008377819875 2-s2.0-0032830832 10509156 \n14 Hensley M. L. Maki R. Venkatraman E. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial Journal of Clinical Oncology 2002 20 12 2824 2831 10.1200/JCO.2002.11.050 2-s2.0-0037096747 12065559 \n15 Takano T. Niikura H. Ito K. Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan International Journal of Clinical Oncology 2014 19 5 897 905 10.1007/s10147-013-0627-5 2-s2.0-84919386754 24149774 \n16 Fenocchio E. Depetris I. Campanella D. Successful treatment of gemcitabine-induced acute interstitial pneumonia with imatinib mesylate: a case report BMC Cancer 2016 16 1 p. 793 10.1186/s12885-016-2833-9 2-s2.0-84991088694 27733144\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6692",
"issue": "2020()",
"journal": "Case reports in obstetrics and gynecology",
"keywords": null,
"medline_ta": "Case Rep Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101576454",
"other_id": null,
"pages": "4629452",
"pmc": null,
"pmid": "32089916",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27733144;30244960;16568459;11105721;30289732;20035385;28747255;31149505;18534250;24149774;12065559;25713428;10509156;31341464;18394689;18614588",
"title": "Grade 4 Pneumonitis in a Patient Treated with a Combination of Gemcitabine and Docetaxel for Recurrent Leiomyosarcoma of the Uterus.",
"title_normalized": "grade 4 pneumonitis in a patient treated with a combination of gemcitabine and docetaxel for recurrent leiomyosarcoma of the uterus"
} | [
{
"companynumb": "US-ACCORD-175142",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "This report describes two patients found to have barium granuloma of the rectum. The lesions appeared as indurated, ulcerated rectal masses that resembled carcinoma on endoscopic examination. Deep mucosal biopsy results demonstrated no malignancy and barium sulfate crystals in tissue macrophages. Radiographs showed persistent soft-tissue barium in the rectum. Past reports of barium granuloma have described ulcerated or polypoid masses in the rectum and anus. Rectal intramural extravasation of barium occurs as a result of asymmetric enema balloon inflation and impaction of the enema tip against the rectal mucosa.",
"affiliations": null,
"authors": "Phelps|J E|JE|;Sanowski|R A|RA|;Kozarek|R A|RA|",
"chemical_list": "D001466:Barium Sulfate",
"country": "United States",
"delete": false,
"doi": "10.1007/BF02603425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3706",
"issue": "24(5)",
"journal": "Diseases of the colon and rectum",
"keywords": null,
"medline_ta": "Dis Colon Rectum",
"mesh_terms": "D000368:Aged; D001466:Barium Sulfate; D003937:Diagnosis, Differential; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006099:Granuloma; D006801:Humans; D008264:Macrophages; D008297:Male; D012002:Rectal Diseases; D012004:Rectal Neoplasms",
"nlm_unique_id": "0372764",
"other_id": null,
"pages": "388-90",
"pmc": null,
"pmid": "7261823",
"pubdate": "1981",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intramural extravasation of barium simulating carcinoma of the rectum.",
"title_normalized": "intramural extravasation of barium simulating carcinoma of the rectum"
} | [
{
"companynumb": "US-BRACCO-2019US00097",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BARIUM SULFATE"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.